Fused pyrrolines which act as ubiquitin-specific protease 30 (usp30) inhibitors

ABSTRACT

The disclosure relates to USP30 Inhibitor Compounds I, pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising same, and medical uses involving same. (I)

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional PatentApplication No. 62/741,945, filed Oct. 5, 2018, the entire contents ofwhich are hereby incorporated by reference.

TECHNICAL FIELD

This disclosure relates to inhibiting Ubiquitin-Specific Protease 30(USP30), including novel compounds and methods for inhibiting USP30. Thecompounds and related methods are useful in the field of medicineincluding the development of new therapies (e.g., for the treatment ofconditions related to the therapeutic inhibition of USP30 such asParkinson's Disease (PD)).

BACKGROUND

The ubiquitination system is a highly regulated process which affects awide variety of cellular activities and physiological processes.Ubiquitination is a reversible process, facilitated by a group ofproteins known as deubiquitinating enzymes (DUBs), which deconjugateubiquitin (Ub) from the substrate. DUBs are encoded by approximately 100human genes and are divided into six families, with the largest familybeing the ubiquitin-specific proteases (USPs) with more than 50 members.

Ubiquitination regulates mitochondrial dynamics and biogenesis,affecting the abundance and function of these organelles. Mitochondriaserve many functions to maintain cell health in mammals, includinggenerating ATP. As mitochondria age they become damaged, losing theirmetabolic functionality, and begin releasing pro-apoptotic proteins.Mitochondria self-regulate their quality via the mechanism of mitophagy,which is the selective removal of damaged mitochondria from the cell.Ubiquitination of mitochondrial proteins is believed to contribute tomitochondrial dynamics in mammalian cells, possibly by “flagging” thoseproteins for inactivation. Ubiquitin-Specific Protease 30 (USP30) isembedded in the outer membrane of mitochondria, where it participates inthe maintenance of mitochondrial morphology. It is believed thatover-expression of USP30 can lead to a decrease in mitophagy.

Inactivating mutations in PINK1 and Parkin can impair mitophagy andresult in accumulation of damaged mitochondria and neuronal toxicity,which has been implicated in Parkinson's Disease. USP30 opposes theligase activity of Parkin and is a negative regulator of mitophagy.USP30 inhibition is expected to promote mitophagy and restoremitochondrial health.

SUMMARY

The disclosure provides compounds useful for inhibiting USP30, includingUSP30 Inhibitor Compounds as defined herein. In some embodiments, thedisclosure provides a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein

R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R_(g) and R^(h) are defined asfollows:

(i) W and Rb form a C₁-C₄ alkylene group between the atoms to which theyare attached, wherein said C₁-C₄ alkylene group is substituted with 0-4substituents selected from the group consisting of halogen, C₁-C₃ alkyl,and C₁-C₃ haloalkyl; and R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h)are each independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃haloalkyl; or

(ii) R^(a) and R^(e) form a C₁-C₂ alkylene group between the atoms towhich they are attached, wherein said C₁-C₂ alkylene group issubstituted with 0-4 substituents selected from the group consisting ofhalogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and R^(b), R^(c), R^(d),R^(f), R^(g), and R^(h) are each independently hydrogen, halogen, C₁-C₃alkyl, or C₁-C₃ haloalkyl; or

(iii) R^(a) and R^(g) form a C₁-C₃ alkylene group between the atoms towhich they are attached, wherein said C₁-C₃ alkylene group issubstituted with 0-4 substituents selected from the group consisting ofhalogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and R^(b), R^(c), R^(d),R^(e), R^(f), and R^(h) are each independently hydrogen, halogen, C₁-C₃alkyl, or C₁-C₃ haloalkyl; or

(iv) R^(h) and R^(c) form a C₁-C₄ alkylene group between the atoms towhich they are attached, wherein said C₁-C₄ alkylene group issubstituted with 0-4 substituents selected from the group consisting ofhalogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and R^(a), R^(d), R^(e),R^(f), R^(g), and R^(h) are each independently hydrogen, halogen, C₁-C₃alkyl, or C₁-C₃ haloalkyl; or

(v) R^(b) and R^(c) form a C₁-C₃ alkylene group between the atoms towhich they are attached, wherein said C₁-C₃ alkylene group issubstituted with 0-4 substituents selected from the group consisting ofhalogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and R^(a), R^(e), R^(d),R^(f), R^(g), and R^(h) are each independently hydrogen, halogen, C₁-C₃alkyl, or C₁-C₃ haloalkyl; or

(vi) R^(b) and R^(g) form a C₁-C₄ alkylene group between the atoms towhich they are attached, wherein said C₁-C₄ alkylene group issubstituted with 0-4 substituents selected from the group consisting ofhalogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and R^(a), R^(e), R^(d),R^(e), R^(f), and R^(h) are each independently hydrogen, halogen, C₁-C₃alkyl, or C₁-C₃ haloalkyl; or

(vii) R^(c) and R^(d) together with the atom to which they are attached,form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6membered cycloalkyl or heterocycloalkyl is substituted with 0-4substituents selected from the group consisting of halogen, C₁-C₃ alkyl,and C₁-C₃ haloalkyl; and R^(a), R^(b), R^(e), R^(f), R^(g), and R^(h)are each independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃haloalkyl; or

(viii) R^(c) and R^(d) together form ═O; and R^(d), R^(b), R^(e), R^(f),R^(g), and R^(h) are each independently hydrogen, halogen, C₁-C₃ alkyl,or C₁-C₃ haloalkyl; or

(ix) R^(c) and R^(c) form a C₁-C₄ alkylene group between the atoms towhich they are attached, wherein said C₁-C₄ alkylene group issubstituted with 0-4 substituents selected from the group consisting ofhalogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and R^(a), R^(b), R^(d),R^(f), R^(g), and R^(h) are each independently hydrogen, halogen, C₁-C₃alkyl, or C₁-C₃ haloalkyl; or

(x) R^(c) and R^(g) form a C₁-C₃ alkylene group between the atoms towhich they are attached, wherein said C₁-C₃ alkylene group issubstituted with 0-4 substituents selected from the group consisting ofhalogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl, and R^(a), R^(b), R^(d),R^(e), R^(f), and R^(h) are each independently hydrogen, halogen, C₁-C₃alkyl, or C₁-C₃ haloalkyl; or

(xi) R^(e) and R^(f) together with the atom to which they are attached,form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6membered cycloalkyl or heterocycloalkyl is substituted with 0-4substituents selected from the group consisting of halogen, C₁-C₃ alkyl,and C₁-C₃ haloalkyl; and R^(a), R^(b), R^(c), R^(d), R^(g), and R^(h)are each independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃haloalkyl; or

(xii) R^(c) and R^(f) together form ═O; and R^(a), R^(b), R^(c), R^(d),R^(g), and R^(h) are each independently hydrogen, halogen, C₁-C₃ alkyl,or C₁-C₃ haloalkyl; or

(xiii) R^(e) and R^(g) form a C₁-C₃ alkylene group between the atoms towhich they are attached, wherein said C₁-C₃ alkylene group issubstituted with 0-4 substituents selected from the group consisting ofhalogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and R^(a), R^(b), R^(c),R^(d), R^(f), and R^(h) are each independently hydrogen, halogen, C₁-C₃alkyl, or C₁-C₃ haloalkyl; or

(xiv) R^(g) and R^(h) together with the atom to which they are attached,form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6membered cycloalkyl or heterocycloalkyl is substituted with 0-4substituents selected from the group consisting of halogen, C₁-C₃ alkyl,and C₁-C₃ haloalkyl; and R^(a), R^(b), R^(c), R^(d), R^(e), and R^(f)are each independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃haloalkyl; or

(xv) R^(g) and R^(h) together form ═O; and R^(a), R^(b), R^(c), R^(d),R^(e), and R^(f) are each independently hydrogen, halogen, C₁-C₃ alkyl,or C₁-C₃ haloalkyl; and

Ar¹ is phenylene or 5-6 membered heteroarylene, wherein said phenyleneor heteroarylene is substituted with m 10 groups; and

Ar² is phenylene or 5-10 membered heteroarylene, wherein said phenyleneor heteroarylene is substituted with n R² groups;

L is —O—, —S—, —NR³—, —C(R⁴)₂—, —S(O)₂—, or —S(O)—;

M is C₁-C₆ alkyl, C₁-C₆ haloalkyl, 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl, wherein said cycloalkyl, phenyl, or heteroarylis substituted with p R⁵ groups;

each occurrence of R¹, R², and R⁵ is independently halo, cyano, NO₂,oxo, hydroxyl, —R⁶, —OR⁶, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, —C₁-C₆ alkylene-R⁶, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, —C₀-C₃alkylene-NR⁶R⁷, —C₀-C₃ alkylene-NR⁷R⁸, —C₀-C₃ alkylene-C(O)NR⁶R⁷, —C₀-C₃alkylene-C(O)NR⁷W, —C₀-C₃ alkylene-NR⁷C(O)R⁶, —C₀-C₃ alkylene-NR⁷C(O)W,—C₀-C₃ alkylene-NR⁷S(O)₂R⁶, —C₀-C₃ alkylene-C(O)R⁶, —C₀-C₃alkylene-C(O)R⁷, —C₀-C₃ alkylene-SR⁶, —C₀-C₃ alkylene-S(O)R⁶, —C₀-C₃alkylene-S(O)₂R⁶, —C₀-C₃ alkylene-S(O)₂R⁷, —C₀-C₃ alkylene-S(O)₂NR⁶R⁷,—C₀-C₃ alkylene-S(O)₂NR⁷R⁸, —C₀-C₃ alkylene-NR⁷C(O)NR⁸R⁹, —C₀-C₃alkylene-NR⁷S(O)₂NR⁸R⁹, —C₀-C₃ alkylene-C(O)OR⁷, —C₀-C₃alkylene-C(O)OR⁶, —C₀-C₃ alkylene-OC(O)R⁷, —C₀-C₃ alkylene-OC(O)R⁶,—C₀-C₃ alkylene-NR⁷C(O)OR⁸, or —C₀-C₃ alkylene-NR⁷S(O)₂R⁸;

R³ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

each R⁴ is independently H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl, or two R⁴groups together with the carbon atom to which they are attached form a3-6 membered cycloalkyl or heterocycloalkyl;

each R⁶ is independently 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, 6-10 membered aryl, or 3-8 membered cycloalkyl,wherein said heteroaryl, heterocycloalkyl, aryl, or cycloalkyl isoptionally substituted with 1-5 substituents independently selected fromthe group consisting of halo, oxo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10membered aryl, 3-8 membered cycloalkyl, —NR¹⁰C(O)NR¹¹R¹², —NR¹⁰R¹¹,—C(O)R¹⁰, —NR¹⁰C(O)R¹¹, —NR¹⁰C(O)OR¹¹, —S(O)₂R¹⁰, —C(O)NR¹⁰R¹¹,—C(O)OR¹⁰, —S(O)₂NR¹⁰R¹¹, —NR¹⁰S(O)₂R¹¹, —OR¹⁰, —OC(O)R¹⁰, —OS(O)₂R¹⁰,—OC(O)NR¹⁰R¹¹, —OC(O)OR¹⁰, —OS(O)₂NR¹⁰R¹¹, —C(O)NR¹⁰C(O)NR¹¹R¹²,—C(O)C(O)R¹⁰, —C(O)NR¹⁰C(O)R¹¹, —C(O)NR¹⁰C(O)OR¹¹, —C(O)S(O)₂R¹⁰,—C(O)C(O)NR¹⁰R¹¹, —C(O)C(O)OR¹⁰, —C(O)S(O)₂NR¹⁰R¹¹, —C(O)NR¹⁰S(O)₂R¹¹,—C₁-C₆ alkylene-R¹⁰, —C₁-C₆ alkylene-NR¹⁰C(O)NR¹¹R¹², —C₁-C₆alkylene-NR¹⁰NR¹¹, —C₁-C₆ alkylene-C(O)R¹⁰, —C₁-C₆ alkylene-NR¹⁰C(O)R¹¹,—C₁-C₆ alkylene-NR¹⁰C(O)OR¹¹, —C₁-C₆ alkylene-S(O)₂R¹⁰, —C₁-C₆alkylene-C(O)NR¹⁰R¹¹, —C₁-C₆ alkylene-C(O)OR¹⁰, —C₁-C₆alkylene-S(O)₂NR¹⁰R¹¹, —C₁-C₆ alkylene-NR¹⁰S(O)₂R¹¹, —C₁-C₆alkenylene-R¹⁰, —C₁-C₆ alkenylene-NR¹⁰C(O)NR¹¹10², —C₁-C₆alkenylene-NR¹⁰R¹¹, —C₁-C₆ alkenylene-C(O)R¹⁰, —C₁-C₆alkenylene-NR¹⁰C(O)R¹¹, —C₁-C₆ alkenylene-NR¹⁰C(O)OR¹¹, —C₁-C₆alkenylene-S(O)₂R¹⁰, —C₁-C₆ alkenylene-C(O)NR¹⁰R¹¹, —C₁-C₆alkenylene-C(O)OR¹⁰, —C₁-C₆ alkenylene-S(O)₂NR¹⁰R¹¹, and —C₁-C₆alkenylene-NR¹⁰S(O)₂R¹¹;

each R⁷, R⁸, and R⁹ is independently hydrogen or C₁-C₆ alkyl;

each R¹⁰, R¹¹, and R¹² is independently hydrogen, C₁-C₆ alkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl,or 3-8 membered cycloalkyl;

m is 0-4;

n is 0-4; and

p is 0-4.

In some embodiments, the disclosure provides a compound of formula(I-C):

or a pharmaceutically acceptable salt thereof, wherein R², R⁵, n, R^(a),R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) are all as definedfor formula (I) above and described in classes and subclasses herein forformula (I), both singly and in combination.

In some embodiments, a USP30 Inhibitor Compound is a compound selectedfrom the group consisting of:

wherein R², R⁵, n, and p are as defined with respect to formula (I)herein, or a pharmaceutically acceptable salt thereof, having an IC₅₀value of about ≤1 μM (and preferably ≤0.5 μM or ≤0.1 04) and >0.001 μMas measured in a Ubiquitin-Rhodamine 110 Assay as described inExample 1. In some embodiments, compounds of formula (I-C) are providedwhere R² and R⁵ are both hydrogen.

In some embodiments, a USP30 Inhibitor Compound is a compound of thechemical formula:

wherein R², R⁵, n, and p are as defined with respect to formula (I)herein, or a pharmaceutically acceptable salt thereof, having an IC₅₀value of about ≤1 μM (and preferably ≤0.5 μM or ≤0.1 μM) and >0.001 μMas measured in a Ubiquitin-Rhodamine 110 Assay as described in Example1.

In some embodiments, a compound is any compound selected from thecompounds listed in Table 1 herein.

DETAILED DESCRIPTION

The present disclosure relates to compounds of formula (I), as definedherein, pharmaceutically acceptable salts thereof, pharmaceuticalcompositions comprising same, and medical uses involving same. In someembodiments, the compounds of formula (I) are USP30 Inhibitor Compounds.In other embodiments, the compounds of formula (I) are useful, forexample, as analytical tools and/or control compounds in biologicalassays (e.g., compounds of any of the following aspects and embodimentsthat are not USP30 Inhibitor Compounds).

USP30 Inhibitor Compounds are useful in the development of new therapiesfor Parkinson's disease (PD), and in methods of treating diseases orconditions by inhibiting USP30 (such as PD). Parkin (E3 ubiquitinligase) and PINK1 (kinase) are key regulators of mitophagy. In healthymitochondria, PINK1 localization to the mitochondrial outer membrane(MOM) and exposure to the cytosol is limited by rapid import to themitochondrial inner membrane (MIM). Once localized to the MIM, PINK1 isprocessed by several proteases, such as presenilin associatedrhomboid-like protease (PARL), to yield a truncated version of PINK1which is subsequently degraded by the proteasome (Meissner et al.,Autophagy. 2015, 11(9), 1484-1498). Upon mitochondrial depolarization ordysfunction, PINK1 accumulates in the MOM, recruiting and activatingParkin via PINK1-dependent phosphorylation of both ubiquitin and Parkin.Consequently, activated Parkin ubiquitinates MOM proteins like TOMM20 totrigger mitophagy (Pickrell et al., Neuron. 2015, 85(2), 257-273). USP30is embedded in the MOM with its catalytic DUB domain oriented towardsthe cytosol and has been shown to antagonize Parkin-mediatedubiquitination of common substrates, consequently opposingParkin-mediated mitophagy. Genetic silencing of USP30 results inincreased ubiquitination of several Parkin substrates followed byincreased mitophagy. In model organisms, USP30 depletion is able torescue mitophagy defects caused by pathogenic Parkin mutations, as wellas restore mitochondria morphology and function, and dopamine levels.(Nakamura, et al., Mol Biol Cell. 2008, 19(5), 1903-1911; Bingol, etal., Nature 2014, 510(7505):370-5). Therefore, inhibition of USP30 witha compound disclosed herein could present a novel treatment paradigm forPD by promoting mitochondrial turnover.

Definitions

As used herein, the term “alkyl” means a substituted or unsubstitutedhydrocarbon chain that is completely saturated, including straight-chainalkyl groups and branched-chain alkyl groups, and that has a singlepoint of attachment to the rest of the molecule. In some embodiments, astraight chain or branched chain alkyl has about 1-20 carbon atoms inits backbone (e.g., C₁-C₂₀ for straight chain, C₂-C₂₀ for branchedchain), and alternatively, about 1-10. In some embodiments, an alkyl hasabout 1-8 carbon atoms. In some embodiments, an alkyl has about 1-6carbon atoms. In some embodiments, an alkyl has about 1-5 carbon atoms.In some embodiments, an alkyl has about 1-4 carbon atoms. In someembodiments, an alkyl has about 1-3 carbon atoms. In some embodiments,an alkyl has about 1-2 carbon atoms.

As used herein, the term “alkylene” refers to a bivalent alkyl group.Exemplary alkylenes include —CH₂—, —CH₂CH₂—, —CH(CH₃)—, —CH₂CH(CH₃)—,—CH(CH₃)CH₃)—, etc. In some embodiments, an “alkylene chain” is apolymethylene group, i.e., —(CH₂)_(n)—, wherein n is a positive integer,preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2to 3. A substituted alkylene chain is a polymethylene group in which oneor more methylene hydrogen atoms are replaced with a substituent.

As used herein, the term “alkenyl” refers to an alkyl group, as definedherein, having one or more double bonds.

As used herein, the term “alkenylene” refers to a bivalent alkenylgroup. A substituted alkenylene chain is a polymethylene groupcontaining at least one double bond in which one or more hydrogen atomsare replaced with a substituent.

As used herein, the term “alkynyl” refers to an alkyl group, as definedherein, having one or more triple bonds.

The term “aryl” refers to ring systems having a total of five tofourteen ring members, wherein at least one ring in the system isaromatic and wherein each ring in the system contains 3 to 7 ringmembers. The term “aryl” may be used interchangeably with the term “arylring.” In certain embodiments of the present disclosure, “aryl” refersto an aromatic ring system and exemplary groups include phenyl,biphenyl, naphthyl, anthracyl and the like, which may bear one or moresubstituents. Also included within the scope of the term “aryl,” as itis used herein, is a group in which an aromatic ring is fused to one ormore non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl,phenanthridinyl, or tetrahydronaphthyl, and the like.

The term “arylene” refers to a bivalent aryl group (e.g., phenylene).

As used herein, the term “cycloalkyl” refers to a cyclic alkyl group(e.g., a monocyclic alkyl group or a bicyclic alkyl group). In someembodiments, “cycloalkyl” refers to a monocyclic C₃-C₈ cycloalkyl group.In some embodiments, “cycloalkyl” refers to a monocyclic C₃-C₆cycloalkyl group.

The terms “halogen” or “halo” mean F, Cl, Br, or I.

The term “heteroaryl” refer to groups having 5 to 10 ring atoms,preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons sharedin a cyclic array; and having, in addition to carbon atoms, from one tofive heteroatoms wherein the term “heteroatom” refers to nitrogen,oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur,and any quaternized form of a basic nitrogen. Exemplary heteroarylgroups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. Theterm “heteroaryl”, as used herein, also includes groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Examplary groups include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted.

The term “heteroarylene” refers to a bivalent heteroaryl group.

As used herein, the term “heterocycloalkyl” refers to a stable 3- to7-membered monocyclic or 7- to 10-membered bicyclic cyclic moiety thatis saturated and having, in addition to carbon atoms, one or more,preferably one to four, heteroatoms independently selected fromnitrogen, oxygen, and sulfur, including any oxidized form of nitrogen orsulfur, and any quaternized form of a basic nitrogen. As an example, ina saturated ring having 1-3 heteroatoms selected from oxygen, sulfur ornitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (asin pyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl). Aheterocycloalkyl ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of suchheterocycloalkyl radicals include tetrahydrofuranyl,tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl,thiazepinyl, morpholinyl, and quinuclidinyl. The term “heterocycloalkyl”also includes groups in which a heterocycloalkyl ring is fused to one ormore aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl,3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, wherethe radical or point of attachment is on the heterocycloalkyl ring.

As used herein, a “USP30 Inhibitor Compound” refers to a compound havingan IC50 of about 1 micromolar or less (i.e., an IC₅₀ value of ≤1 μMand >0.001 μM) in the Ubiquitin-Rhodamine 110 Assay for USP30 asdescribed in Example 1 herein. For example, a USP30 Inhibitor can be acompound of formula (I) having an IC₅₀ value of ≤0.5 μM and >0.001 μMwhen tested in the Biochemical Assay of Example 1. In some embodiments,a USP30 Inhibitor is a compound of formula (I) having an IC₅₀ value of≤0.1 μM and >0.001 μM when tested in the Biochemical Assay of Example 1.

As used herein, the term “pharmaceutically acceptable salt” refers tosalts of such compounds that are appropriate for use in pharmaceuticalcontexts, i.e., salts which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue toxicity, irritation, allergic response andthe like, and are commensurate with a reasonable benefit/risk ratio.Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describes pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).

Unless otherwise stated, all chemical structures and chemical namesdepicted herein without stereochemical descriptors shall be understoodto include all stereoisomeric (e.g., enantiomeric or diastereomeric)forms of the compound depicted by the structure or name, as well as allgeometric and conformational isomeric forms of the compound; forexample, the R and S configurations for each stereocenter. Unlessotherwise stated, such structures and names shall be understood toinclude a stereochemically pure form of the compound and any mixture ofenantiomers, diastereomers, or geometric (or conformational) isomers.Unless otherwise stated, all tautomeric forms of the compounds of thedisclosure are within the scope of the disclosure.

Unless otherwise stated, all chemical structures and chemical namesdepicted herein with stereochemical descriptors (i.e., hash and wedgebonds in the chemical structures; (R)- and (S)-designators in thechemical names) shall be understood to refer to a compound having therelative stereochemistry (but not necessarily the absolutestereochemistry) indicated by the stereochemical descriptors. Unlessotherwise stated, such structures and names shall be understood toinclude an enantiomerically pure form of the compound having therelative stereochemistry indicated by the stereochemical descriptors orany mixture of enantiomers. In some embodiments, the enantiomers arepresent in a racemic mixture. In other embodiments, the enantiomerhaving the absolute stereochemistry suggested by the stereochemicaldescriptors is present in substantially enantiomerically pure form. Inother embodiments, the enantiomer having the absolute stereochemistryopposite to that suggested by the stereochemical descriptors is presentin substantially enantiomerically pure form.

Unless otherwise stated, all chemical structures and chemical namesdepicted herein with stereochemical descriptors (i.e., hash and wedgebonds in the chemical structures; (R)- and (S)-designators in thechemical names) and an “absolute” descriptor (“abs”) shall be understoodto refer to a compound having the absolute stereochemistry indicated bythe stereochemical descriptors. Unless otherwise stated, such structuresand names shall be understood to include the compound inenantiomerically pure form or in a mixture with its enantiomer. In someembodiments, the enantiomers are present in a racemic mixture. In otherembodiments, the enantiomer having the absolute stereochemistryindicated by the stereochemical descriptors is present in substantiallyenantiomerically pure form.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this disclosure.

It will be appreciated that throughout the present disclosure, unlessotherwise indicated, reference to a compound of formula (I) is intendedto also include formulas I-1, I-2, I-3, I-4, I-A, I-A-1, I-A-2, I-A-3,I-A-4, I-B, I-B-1, I-B-2, I-B-3, I-B-4, I-C, I-C-1, I-C-2, I-C-3, I-C-4,I-C-a, I-C-b, I-C-c, I-C-d, I-C-e, I-C-f, I-D, I-E, I-E-1, I-E-2, I-E-3,I-E-4, I-F-1, I-F-2, I-G-1, I-G-2, I-H-1, I-H-2, I-J-1, I-J-2, I-K-1,I-K-2, I-L-1, I-L-2, I-M, I-M-1, I-M-2, I-M-3, and I-M-4, and compoundspecies of such formulas disclosed herein.

Compounds of the Disclosure

In one aspect, the disclosure relates to a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein Ar¹, Ar², M, L,R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) are all asdefined for formula (I) above.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-1):

wherein Ar¹, Ar², M, L, R^(a), R^(d), R^(e), R^(f), R^(g), and R^(h) areall as defined for formula (I) above and described in classes andsubclasses herein for formula (I), both singly and in combination, and

-   wherein R, R^(k), R¹, and Rn are each independently hydrogen,    halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-2):

wherein Ar¹, Ar², M, L, R^(a), R^(d), R^(e), R^(f), R^(g), and R^(h) areall as defined for formula (I) above and described in classes andsubclasses herein for formula (I), both singly and in combination, and

-   wherein R¹ and R^(k) are each independently hydrogen, halogen, C₁-C₃    alkyl, or C₁-C₃ haloalkyl.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-3)

wherein Ar¹, Ar², M, L, R^(a), R^(d), R^(e), R^(f), R^(g), and R^(h) areall as defined for formula (I) above and described in classes andsubclasses herein for formula (I), both singly and in combination, and

-   wherein R^(j), R^(k), R^(m), R^(n), R^(o), and R^(p) are each    independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-4)

wherein Ar¹, Ar², M, L, R^(a), R^(b), R^(d), R^(f), R_(g) and R^(h) areall as defined for formula (I) above and described in classes andsubclasses herein for formula (I), both singly and in combination, and

-   wherein R^(q) and R^(r) are each independently hydrogen, halogen,    C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In another aspect, the disclosure relates to a compound of formula(I-A):

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is C or N;

X² is CH, CR¹, O, S, N, NH, or NR¹, as valency permits;

X³ is CH, CR¹, O, S, N, NH, or NR¹, as valency permits;

X⁴ is C or N;

X⁵ is a bond, CH, CR¹, O, S, N, NH, or NR¹, as valency permits;

X⁶ is CH, CR¹, O, S, N, NH, or NR¹, as valency permits;

Y¹ is C or N;

Y² is C or N;

Y³ is CH, CR², O, S, N, NH, or NR², as valency permits;

Y⁴ is a bond, CH, CR², O, S, N, NH, or NR², as valency permits;

Y⁵ is CH, CR², O, S, N, NH, or NR², as valency permits;

Y⁶ is CH, CR², O, S, N, NH, or NR², as valency permits,

provided that the ring comprising X¹, X², X³, X⁴, X⁵, and X⁶ isaromatic, and

that the ring comprising Y¹, Y², Y³, Y⁴, Y⁵ and Y⁶ is aromatic;

-   and wherein L, M, R¹, R², R⁵, R^(a), R^(b), R^(c), R^(d), R^(e),    R^(f), R^(g), and R^(h) are are all as defined for formula (I) above    and described in classes and subclasses herein for formula (I), both    singly and in combination.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-A-1):

wherein M, L, X¹, X², X³, X⁴, X⁵, X⁶, Y¹, Y², Y³, Y⁴, Y⁵, R^(a), R^(d),R^(e), R^(f), R^(g), and R^(h) are all as defined for formula (I-A)above and described in classes and subclasses herein for formula (I-A),both singly and in combination, and

-   wherein R^(j), R^(k), R^(m), and R^(n) are each independently    hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-A-2):

wherein M, L, X¹, X², X³, X⁴, X⁵, X⁶, Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, R^(a),R^(d), R^(e), R^(f), R^(g) and R^(h) are all as defined for formula(I-A) above and described in classes and subclasses herein for formula

(I-A), both singly and in combination, and

-   wherein R^(j) and R^(k) are each independently hydrogen, halogen,    C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-A-3):

wherein M, L, X¹, X², X³, X⁴, X⁵, X⁶, Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, R^(a),R^(d), R^(e), R^(f), R^(g), and R^(h) are all as defined for formula(I-A) above and described in classes and subclasses herein for formula

(I-A), both singly and in combination, and

-   wherein R^(j), R^(k), R^(m), R^(n), R^(o), and R^(p) are each    independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-A-4):

wherein M, L, X¹, X², X³, X⁴, X⁵, X⁶, Y¹, Y², Y⁴, Y⁶, R^(a), R^(b),R^(d), R^(f), R^(g) and R^(h) are all as defined for formula (I-A) aboveand described in classes and subclasses herein for formula

(I-A), both singly and in combination, and

-   wherein R^(q) and R^(r) are each independently hydrogen, halogen,    C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In another aspect, the disclosure relates to a compound of formula(I-B):

or a pharmaceutically acceptable salt thereof, wherein:

Y³ is CH, CR², or N;

Y⁴ is CH, CR², or N;

Y⁵ is CH, CR², or N;

Y⁶ is CH, CR², or N; and

-   wherein X¹, X², X³, X⁴, X⁶, L, M, R^(a), R^(b), R^(c), R^(d), R^(e),    R^(f), R^(g) and R^(h) are all as defined for formula (I) above and    described in classes and subclasses herein for formula (I-A), both    singly and in combination.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-B-1):

wherein M, L, X¹, X², X³, X⁴, X⁶, Y³, Y⁴, Y⁵, Y⁶, R^(a), R^(d), R^(e),R^(f), R^(g), and R^(h) are all as defined for formula (I-B) above anddescribed in classes and subclasses herein for formula (I-B), bothsingly and in combination, and

-   wherein R^(j), R^(k), R^(m), and R^(n) are each independently    hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-B-2):

wherein M, L, X¹, X², X³, X⁴, X⁶, Y³, Y⁴, Y⁵, Y⁶, R^(a), R^(d), R^(e),R^(f), R^(g), and R^(h) are all as defined for formula (I-B) above anddescribed in classes and subclasses herein for formula (I-B), bothsingly and in combination, and

-   wherein R^(j) and R^(k) are each independently hydrogen, halogen,    C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-B-3):

wherein M, L, X¹, X², X³, X⁴, X⁶, Y³, Y⁴, Y⁵, Y⁶, R^(a), R^(d), R^(e),R^(f), R^(g), and R^(h) are all as defined for formula (I-B) above anddescribed in classes and subclasses herein for formula (I-B), bothsingly and in combination, and

-   wherein R^(j), R^(k), R^(m), R^(n), R^(o), and R^(p) are each    independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-B-4):

wherein M, L, X¹, X², X³, X⁴, X⁶, Y³, Y⁴, Y⁵, Y⁶, R^(a), R^(d), R^(e),R^(f), R^(g), and R^(h) are all as defined for formula (I-B) above anddescribed in classes and subclasses herein for formula (I-B), bothsingly and in combination, and

-   wherein R^(q) and R^(r) are each independently hydrogen, halogen,    C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In another aspect, the disclosure relates to a compound of formula(I-C):

or a pharmaceutically acceptable salt thereof, wherein R², R⁵, n, p,R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g) and R^(h) are are all asdefined for formula (I) above and described in classes and subclassesherein for formula (I), both singly and in combination.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-C-1):

wherein R², R⁵, n, p, R^(a), R^(d), R^(e), R^(f), R^(g), and R^(h) areall as defined for formula (I-C) above and described in classes andsubclasses herein for formula (I-C), both singly and in combination, and

-   wherein R^(j), R^(k), R^(m), and R^(n) are each independently    hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-C-2):

wherein R², R⁵, n, p, R^(a), R^(d), R^(e), R^(f), R^(g), and R^(h) areall as defined for formula (I-C) above and described in classes andsubclasses herein for formula (I-C), both singly and in combination, and

-   wherein R^(j) and R^(k) are each independently hydrogen, halogen,    C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-C-3):

wherein R², R⁵, n, p, R^(a), R^(d), R^(e), R^(f), R^(g), and R^(h) areall as defined for formula (I-C) above and described in classes andsubclasses herein for formula (I-C), both singly and in combination, and

-   wherein R^(j), R^(k), R^(m), R^(n), R^(o), and R^(p) are each    independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-C-4):

wherein R², R⁵, n, p, R^(a), R^(b), R^(d), R^(f), R^(g), and R^(h) areall as defined for formula (I-C) above and described in classes andsubclasses herein for formula (I-C), both singly and in combination, and

-   wherein R^(q) and R^(r) are each independently hydrogen, halogen,    C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In some embodiments, the disclosure relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein thecompound is of formula (I-C-a):

wherein R², R⁵, n, and p are all as defined for formula (I-C) above anddescribed in classes and subclasses herein for formula (I-C), bothsingly and in combination.

In some embodiments, the disclosure relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein thecompound is of formula (I-C-b):

wherein R², R⁵, n, and p are all as defined for formula (I-C) above anddescribed in classes and subclasses herein for formula (I-C), bothsingly and in combination.

In some embodiments, the disclosure relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein thecompound is of formula (I-C-c):

wherein R², R⁵, n, and p are all as defined for formula (I-C) above anddescribed in classes and subclasses herein for formula (I-C), bothsingly and in combination.

In some embodiments, the disclosure relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein thecompound is of formula (I-C-d):

wherein R², R⁵, n, and p are all as defined for formula (I-C) above anddescribed in classes and subclasses herein for formula (I-C), bothsingly and in combination.

In some embodiments, the disclosure relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein thecompound is of formula (I-C-e):

wherein R², R⁵, n, and p are all as defined for formula (I-C) above anddescribed in classes and subclasses herein for formula (I-C), bothsingly and in combination.

In some embodiments, the disclosure relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein thecompound is of formula (I-C-f):

wherein R², R⁵, n, and p are all as defined for formula (I-C) above anddescribed in classes and subclasses herein for formula (I-C), bothsingly and in combination.

In another aspect, the disclosure relates to a compound of formula(I-D):

or a pharmaceutically acceptable salt thereof, wherein R^(a), R^(b),R^(c), R^(d), R^(e), R^(f), R^(g) and R^(h) are all as defined forformula (I) above and described in classes and subclasses herein forformula (I), both singly and in combination.

In another aspect, the disclosure relates to a compound of formula(I-E):

or a pharmaceutically acceptable salt thereof, wherein R^(a), R^(b),R^(c), R^(d), R^(e), R^(f) and R^(g) are all as defined for formula (I)above and described in classes and subclasses herein for formula (I),both singly and in combination. In some embodiments, the presentdisclosure provides compounds, or pharmaceutically acceptable saltsthereof, of formula (I-E-1):

In some embodiments, the compound of formula (I-E-1) has the absolutestereochemistry of the first eluting isomer when a racemic mixture ofthe compound of formula (I-E-1) is separated by the procedure describedin Example 3, Step 6. In some embodiments, the compound of formula(I-E-1) has the absolute stereochemistry of the second eluting isomerwhen a racemic mixture of the compound of formula (I-E-1) is separatedby the procedure described in Example 3, Step 6.

In some embodiments, the compound of formula (I-E-1) is:

In some embodiments, the compound of formula (I-E-1) is:

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-E-2):

In some embodiments, the compound of formula (I-E-2) has the absolutestereochemistry of the first eluting isomer when a racemic mixture ofthe compound of formula (I-E-2) is separated by the procedure describedin Example 4, Step 6. In some embodiments, the compound of formula(I-E-2) has the absolute stereochemistry of the second eluting isomerwhen a racemic mixture of the compound of formula (I-E-2) is separatedby the procedure described in Example 4, Step 6.

In some embodiments, the compound of formula (I-E-2) is:

In some embodiments, the compound of formula (I-E-2) is:

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-E-3):

In some embodiments, the compound of formula (I-E-3) has the absolutestereochemistry of the first eluting isomer when a racemic mixture ofthe compound of formula (I-E-3) is separated by the procedure describedin Example 2, Step 7. In some embodiments, the compound of formula(I-E-3) has the absolute stereochemistry of the second eluting isomerwhen a racemic mixture of the compound of formula (I-E-3) is separatedby the procedure described in Example 2, Step 7.

In some embodiments, the compound of formula (I-E-3) is:

In some embodiments, the compound of formula (I-E-3) is:

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-E-4):

In some embodiments, the compound of formula (I-E-4) has the absolutestereochemistry of the first eluting isomer when a racemic mixture ofthe compound of formula (I-E-4) is separated by the procedure describedin Example 2, Step 7. In some embodiments, the compound of formula(I-E-4) has the absolute stereochemistry of the second eluting isomerwhen a racemic mixture of the compound of formula (I-E-4) is separatedby the procedure described in Example 2, Step 7.

In some embodiments, the compound of formula (I-E-4) is:

In some embodiments, the compound of formula (I-E-4) is:

In another aspect, the disclosure relates to a compound of formula(I-F-1) or (I-F-2):

or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, X⁴,X⁵, X⁶, Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, L, and M are all as defined for formula(I-A) above and described in classes and subclasses herein for formula(I-A), both singly and in combination.

In some embodiments, the compounds of formula (I-F-1) and (I-F-2) arepresent in a racemic mixure. In other embodiments, the compound offormula (I-F-1) or (I-F-2) is present in substantially enantiomericallypure form. The compounds of formula (I-F-1) and (I-F-2) can be separatedfrom one another by chiral HPLC, such as by the procedure described inExample 2, Step 7 or Example 3, Step 6.

In another aspect, the disclosure relates to a compound of formula(I-G-1) or (I-G-2):

or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, X⁴,X⁵, X⁶, Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, L, and M are all as defined for formula(I-A) above and described in classes and subclasses herein for formula(I-A), both singly and in combination.

In some embodiments, the compounds of formula (I-G-1) and (I-G-2) arepresent in a racemic mixure. In other embodiments, the compound offormula (I-G-1) or (I-G-2) is present in substantially enantiomericallypure form. The compounds of formula (I-G-1) and (I-G-2) can be separatedfrom one another by chiral HPLC, such as by the procedure described inExample 2, Step 7, or Example 4, Step 6.

In another aspect, the disclosure relates to a compound of formula(I-H-1) or (I-H-2):

or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, X⁴,X⁵, X⁶, Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, L, and M are all as defined for formula(I-A) above and described in classes and subclasses herein for formula(I-A), both singly and in combination.

In some embodiments, the compounds of formula (I-H-1) and (I-H-2) arepresent in a racemic mixure. In other embodiments, the compound offormula (I-H-1) or (I-H-2) is present in substantially enantiomericallypure form. The compounds of formula (I-H-1) and (I-H-2) can be separatedfrom one another by chiral HPLC, such as by the procedure described inExample 2, Step 7.

In another aspect, the disclosure relates to a compound of formula(I-J-1) or (I-J-2):

or a pharmaceutically acceptable salt thereof, wherein X¹, X², X³, X⁴,X⁵, X⁶, Y¹, Y², Y⁴, Y⁵, Y⁶, L, and M are all as defined for formula(I-A) above and described in classes and subclasses herein for formula(I-A), both singly and in combination.

In some embodiments, the compounds of formula (I-J-1) and (I-J-2) arepresent in a racemic mixure. In other embodiments, the compound offormula (I-J-1) or (I-J-2) is present in substantially enantiomericallypure form. The compounds of formula (I-J-1) and (I-J-2) can be separatedfrom one another by chiral HPLC, such as by the procedure described inExample 2, Step 7.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-K-1) or(I-K-2):

wherein M, L, X¹, X², X³, X⁴, X⁵, X⁶, Y¹, Y², Y³, Y⁴, Y⁵, and Y⁶ are allas defined for formula (I-A) above and described in classes andsubclasses herein for formula (I-A), both singly and in combination.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-L-1) or(I-L-2):

wherein M, L, X¹, X², X³, X⁴, X⁵, X⁶, Y¹, Y², Y³, Y⁴, Y⁵, and Y⁶ are allas defined for formula (I-A) above and described in classes andsubclasses herein for formula (I-A), both singly and in combination.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-M):

wherein M, L, X¹, X², X³, X⁴, X⁵, X⁶, R^(a), R^(b), R^(c), R^(d), R^(e),R^(f), R^(g), and R^(h) are all as defined for formula (I) and (I-A)above and described in classes and subclasses herein for formula (I) and(I-A), both singly and in combination.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-M-1):

wherein M, L, X¹, X², X³, X⁴, X⁵, X⁶, R^(a), R^(d), R^(e), R^(f), R^(g),and R^(h) are all as defined for formula (I-M) above and described inclasses and subclasses herein for formula (I-M), both singly and incombination, and

-   wherein R^(j), R^(k), R^(m), and R^(n) are each independently    hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-M-2):

wherein M, L, X¹, X², X³, X⁴, X⁵, R^(a), R^(d), R^(e), R^(f), R^(g), andR^(h) are all as defined for formula (I-M) above and described inclasses and subclasses herein for formula (I-M), both singly and incombination, and

-   wherein R^(j) and R^(k) are each independently hydrogen, halogen,    C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-M-3):

wherein M, L, X¹, X², X³, X⁴, X⁵, R^(a), R^(d), R^(e), R^(f), R^(g), andR^(h) are all as defined for formula (I-M) above and described inclasses and subclasses herein for formula (I-M), both singly and incombination, and

-   wherein R^(j), R^(k), R^(m), R^(n), R^(o), and R^(p) are each    independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In some embodiments, the present disclosure provides compounds, orpharmaceutically acceptable salts thereof, of formula (I-M-4):

wherein M, L, X¹, X², X³, X⁵, X⁶, R^(a), R^(b), R^(d), R^(f), R^(g), andR^(h) are all as defined for formula (I-M) above and described inclasses and subclasses herein for formula (I-M), both singly and incombination, and

-   wherein R^(q) and R^(r) are each independently hydrogen, halogen,    C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In some embodiments, the disclosure relates to a compound of formula(I), (I-1), (I-2), (I-3), or (I-4), or a pharmaceutically acceptablesalt thereof, wherein Ar¹ is independently phenylene or 5-6 memberedheteroarylene, wherein said phenylene or heteroarylene is substitutedwith m R¹ groups. In some embodiments, Ar¹ is phenylene substituted withm R¹ groups. In some embodiments, Ar¹ is phenylene substituted with 1-2R¹ groups selected from the group consisting of halo, cyano, hydroxyl,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ hydroxyalkyl. Insome embodiments, Ar¹ is phenylene. In some embodiments, Ar¹ is 5-6membered heteroarylene substituted with m R¹ groups. In someembodiments, Ar¹ is 5-6 membered heteroarylene substituted with 1-2 R¹groups selected from the group consisting of halo, cyano, hydroxyl,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ hydroxyalkyl. Insome embodiments, Ar¹ is 5-membered heteroarylene substituted with m R¹groups. In some embodiments, Ar¹ is pyrazole. In some embodiments, Ar¹is thiazole. In some embodiments, Ar¹ is 6-membered heteroarylenesubstituted with m R¹ groups.

In some embodiments, the disclosure relates to a compound of formula(I), (I-1), (I-2), (I-3), (I-4), (I-M), (I-M-1), (I-M-2), (I-M-3), or(I-M-4), or a pharmaceutically acceptable salt thereof, wherein Ar² isindependently phenylene or 5-10 membered heteroarylene, wherein saidphenylene or heteroarylene is substituted with n R² groups. In someembodiments, Ar² is phenylene or 5-6 membered heteroarylene, whereinsaid phenylene or heteroarylene is substituted with n R² groups. In someembodiments, Ar² is phenylene substituted with n R² groups. In someembodiments, Ar² is phenylene substituted with 1-2 R² groups selectedfrom the group consisting of halo, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ hydroxyalkyl. In some embodiments,Ar² is phenylene. In some embodiments, Ar² is 5-10 memberedheteroarylene substituted with n R² groups. In some embodiments, Ar² is5-6 membered heteroarylene substituted with n R² groups. In someembodiments, Ar² is 5-6 membered heteroarylene substituted with 1-2 R²groups selected from the group consisting of halo, cyano, hydroxyl,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ hydroxyalkyl. Insome embodiments, Ar² is 5-membered heteroarylene substituted with n R²groups. In some embodiments, Ar² is 6-membered heteroarylene substitutedwith n R² groups. In some embodiments, Ar² is pyridine. In someembodiments, Ar² is 7-membered heteroarylene substituted with n R²groups. In some embodiments, Ar² is 8-membered heteroarylene substitutedwith n R² groups. In some embodiments, Ar² is 9-membered heteroarylenesubstituted with n R² groups. In some embodiments, Ar² is 10-memberedheteroarylene substituted with n R² groups.

In some embodiments, the disclosure relates to a compound of formula(I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3),(I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2),(I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2),(I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or apharmaceutically acceptable salt thereof, wherein L is —O—, —S—, —NR³—,—C(R⁴)₂—, —S(O)₂—, or —S(O)—. In some embodiments, L is —O—, —S—, or—NH—. In some embodiments, L is —O—. In some embodiments, L is —S—. Insome embodiments, L is —NR³—. In some embodiments, L is —NH—. In someembodiments, L is —C(R⁴)₂—. In some embodiments, L is —CH₂—. In someembodiments, L is —S(O)₂—. In some embodiments, L is —S(O)—.

In some embodiments, the disclosure relates to a compound of formula(I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3),(I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2),(I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2),(I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or apharmaceutically acceptable salt thereof, wherein M is C₁-C₆ alkyl,C₁-C₆ haloalkyl, 3-6 membered cycloalkyl, phenyl, or 5-6 memberedheteroaryl, wherein said cycloalkyl, phenyl, or heteroaryl issubstituted with p R⁵ groups. In some embodiments, M is 3-6 memberedcycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said cycloalkyl,phenyl, or heteroaryl is substituted withp R⁵ groups. In someembodiments, M is C₁-C₆ alkyl. In some embodiments, M is C₁-C₆haloalkyl. In some embodiments, M is 3-6 membered cycloalkyl substitutedwithp R⁵ groups. In some embodiments, M is 3-6 membered cycloalkyl. Insome embodiments, M is 3-6 membered cycloalkyl substituted with 1-2 R⁵groups selected from the group consisting of halo, cyano, hydroxyl,C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ hydroxyalkyl. In someembodiments, M is phenyl substituted withp R⁵ groups. In someembodiments, M is phenyl. In some embodiments, M is phenyl substitutedwith 1-2 R⁵ groups selected from the group consisting of halo, cyano,hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, and C₁-C₆hydroxyalkyl. In some embodiments, M is phenyl substituted with fluoro.In some embodiments, M is 5-6 membered heteroaryl substituted withp R⁵groups. In some embodiments, M is 5-6 membered heteroaryl. In someembodiments, M is 5-6 membered heteroaryl substituted with 1-2 R⁵ groupsselected from the group consisting of halo, cyano, hydroxyl, C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ hydroxyalkyl.

In some embodiments, the disclosure relates to a compound of formula(I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3),(I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-C), (I-C-1),(I-C-2), (I-C-3), (I-C-4), (I-C-a), (I-C-b), (I-C-c), (I-C-d), (I-C-e),(I-C-f), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1),(I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2),(I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof,wherein each occurrence of R¹, R², and R⁵ is independently halo, cyano,NO₂, oxo, hydroxyl, —R⁶, —OR⁶, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, —C₁-C₆ alkylene-R⁶, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, —C₀-C3alkylene-NR⁶R⁷, —C₀-C₃ alkylene-NR⁷R⁸, —C₀-C₃ alkylene-C(O)NR⁶R⁷, —C₀-C₃alkylene-C(O)NR⁷R⁸, —C₀-C₃ alkylene-NR⁷C(O)R⁶, —C₀-C₃alkylene-NR⁷C(O)R⁸, —C₀-C₃ alkylene-NR⁷S(O)₂R⁶, —C₀-C₃ alkylene-C(O)R⁶,—C₀-C₃ alkylene-C(O)R⁷, —C₀-C₃ alkylene-SR⁶, —C₀-C₃ alkylene-S(O)R⁶,—C₀-C₃ alkylene-S(O)₂R⁶, —C₀-C₃ alkylene-S(O)₂R⁷, —C₀-C₃alkylene-S(O)₂NR⁶R⁷, —C₀-C₃ alkylene-S(O)₂NR⁷R⁸, —C₀-C₃alkylene-NR⁷C(O)NR⁸R⁹, —C₀-C₃ alkylene-NR⁷S(O)₂NR⁸R⁹, —C₀-C₃alkylene-C(O)OR⁷, —C₀-C₃ alkylene-C(O)OR⁶, —C₀-C₃ alkylene-OC(O)R⁷,—C₀-C₃ alkylene-OC(O)R⁶, —C₀-C₃ alkylene-NR⁷C(O)OR⁸, or —C₀-C₃alkylene-NR⁷S(O)₂R⁸. In some embodiments, each occurrence of le isindependently halo, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, and C₁-C₆ hydroxyalkyl. In some embodiments, each occurrenceof R¹ is independently halo (e.g., fluoro, chloro, bromo, or iodo). Insome embodiments, each occurrence of R¹ is fluoro. In some embodiments,each occurrence of R¹ is cyano. In some embodiments, each occurrence ofR¹ is hydroxyl. In some embodiments, each occurrence of R¹ is C₁-C₆alkyl. In some embodiments, each occurrence of R¹ is C₁-C₆ alkoxy. Insome embodiments, each occurrence of R¹ is C₁-C₆ haloalkyl. In someembodiments, each occurrence of R¹ is C₁-C₆ hydroxyalkyl. In someembodiments, each occurrence of R² is independently halo, cyano,hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆hydroxyalkyl. In some embodiments, each occurrence of R² isindependently halo (e.g., fluoro, chloro, bromo, or iodo). In someembodiments, each occurrence of R² is fluoro. In some embodiments, eachoccurrence of R² is cyano. In some embodiments, each occurrence of R² ishydroxyl. In some embodiments, each occurrence of R² is C₁-C₆ alkyl. Insome embodiments, each occurrence of R² is C₁-C₆ alkoxy. In someembodiments, each occurrence of R² is C₁-C₆ haloalkyl. In someembodiments, each occurrence of R² is C₁-C₆ hydroxyalkyl. In someembodiments, each occurrence of R⁵ is independently halo, cyano,hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆hydroxyalkyl. In some embodiments, each occurrence of R⁵ isindependently halo (e.g., fluoro, chloro, bromo, or iodo). In someembodiments, each occurrence of R⁵ is fluoro. In some embodiments, eachoccurrence of R⁵ is cyano. In some embodiments, each occurrence of R⁵ ishydroxyl. In some embodiments, each occurrence of R⁵ is C₁-C₆ alkyl. Insome embodiments, each occurrence of R⁵ is C₁-C₆ alkoxy. In someembodiments, each occurrence of R⁵ is C₁-C₆ haloalkyl. In someembodiments, each occurrence of R⁵ is C₁-C₆ hydroxyalkyl.

In some embodiments, the disclosure relates to a compound of formula(I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3),(I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2),(I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2),(I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or apharmaceutically acceptable salt thereof, wherein R³ is H, C₁-C₆ alkyl,or C₁-C₆ haloalkyl. In some embodiments, R³ is H. In some embodiments,R³ is C₁-C₆ alkyl. In some embodiments, R³ is C₁-C₆ haloalkyl.

In some embodiments, the disclosure relates to a compound of formula(I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3),(I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2),(I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2),(I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or apharmaceutically acceptable salt thereof, wherein each R⁴ isindependently H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl, or two R⁴ groupstogether with the carbon atom to which they are attached form a 3-6membered cycloalkyl or heterocycloalkyl. In some embodiments, each R⁴ isH. In some embodiments, two R⁴ groups together with the carbon atom towhich they are attached form a 3-6 membered cycloalkyl. In someembodiments, two R⁴ groups together with the carbon atom to which theyare attached form a 3-6 membered heterocycloalkyl.

In some embodiments, the disclosure relates to a compound of formula(I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3),(I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-C), (I-C-1),(I-C-2), (I-C-3), (I-C-4), (I-C-a), (I-C-b), (I-C-c), (I-C-d), (I-C-e),(I-C-f), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2),(I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or(I-M-4), or a pharmaceutically acceptable salt thereof, wherein each R⁶is 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10membered aryl, or 3-8 membered cycloalkyl, wherein said heteroaryl,heterocycloalkyl, aryl, or cycloalkyl is optionally substituted with 1-5substituents independently selected from the group consisting of halo,oxo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, 3-8membered cycloalkyl, —NR¹⁰C(O)NR¹¹R¹², —NR¹⁰R¹¹, —C(O)R¹⁰, —NR¹⁰C(O)R¹¹,—NR¹⁰C(O)OR¹¹, —S(O)₂R¹⁰, —C(O)NR¹⁰R¹¹, —C(O)OR¹⁰, —S(O)₂NR¹⁰R¹¹,—NR¹⁰S(O)₂R¹¹, —OR¹⁰, —OC(O)R¹⁰, —OS(O)₂R¹⁰, —OC(O)NR¹⁰R¹¹, —OC(O)OR¹⁰,—OS(O)₂NR¹⁰R¹¹, —C(O)NR¹⁰C(O)NR¹¹R¹², —C(O)C(O)R¹⁰, —C(O)NR¹⁰C(O)R¹¹,—C(O)NR¹⁰C(O)OR¹¹, —C(O)S(O)₂R¹⁰, —C(O)C(O)NR¹⁰R¹¹, —C(O)C(O)OR¹⁰,—C(O)S(O)₂NR¹⁰R¹¹, —C(O)NR¹⁰S(O)₂R¹¹, —C₁-C₆ alkylene-R¹⁰, —C₁-C₆alkylene-NR¹⁰C(O)NR¹¹R¹², —C₁-C₆ alkylene-NR¹⁰R¹¹, —C₁-C₆alkylene-C(O)R¹⁰, —C₁-C₆ alkylene-NR¹⁰C(O)R¹¹, —C₁-C₆alkylene-NR¹⁰C(O)OR¹¹, —C₁-C₆ alkylene-S(O)₂R¹⁹, —C₁-C₆alkylene-C(O)NR¹⁰R¹¹, —C₁-C₆ alkylene-C(O)OR¹⁰, —C₁-C₆alkylene-S(O)₂NR¹⁰R¹¹, —C₁-C₆ alkylene-NR¹⁰S(O)₂R¹¹, —C₁-C₆alkenylene-R¹⁰, —C₁-C₆ alkenylene-NR¹⁰C(O)NR¹¹R¹², —-C₁-C₆alkenylene-NR¹⁰R¹¹, —C₁-C₆ alkenylene-C(O)R¹⁰, —C₁-C₆alkenylene-NR¹⁰C(O)R¹¹, —C₁-C₆ alkenylene-NR¹⁰C(O)OR¹¹, —C₁-C₆alkenylene-S(O)₂R¹⁰, —C₁-C₆ alkenylene-C(O)NR¹⁰R¹¹, —C₁-C₆alkenylene-C(O)OR¹⁰, —C₁-C₆ alkenylene-S(O)₂NR¹⁰R¹¹, and —C₁-C₆alkenylene-NR¹⁹S(O)₂R¹¹. In some embodiments, each R⁶ is independentlyoptionally substituted 5-10 membered heteroaryl. In some embodiments,each R⁶ is independently optionally substituted 4-10 memberedheterocycloalkyl. In some embodiments, each R⁶ is independentlyoptionally substituted 6-10 membered aryl. In some embodiments, each R⁶is independently optionally substituted 3-8 membered cycloalkyl.

In some embodiments, the disclosure relates to a compound of formula(I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3),(I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-C), (I-C-1),(I-C-2), (I-C-3), (I-C-4), (I-C-a), (I-C-b), (I-C-c), (I-C-d), (I-C-e),(I-C-f), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1),(I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2),(I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof,wherein each R⁷, R⁸, and R⁹ is independently hydrogen or C₁-C₆ alkyl. Insome embodiments, each R⁷, R⁸, and R⁹ is independently hydrogen.

In some embodiments, the disclosure relates to a compound of formula(I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3),(I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-C), (I-C-1),(I-C-2), (I-C-3), (I-C-4), (I-C-a), (I-C-b), (I-C-c), (I-C-d), (I-C-e),(I-C-f), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1),(I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2),(I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof,wherein each R¹⁰, R¹¹, and R¹² is independently hydrogen, C₁-C₆ alkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 memberedaryl, or 3-8 membered cycloalkyl. In some embodiments, each R¹⁻⁹, R^(H),and R¹² is independently hydrogen.

In some embodiments, the disclosure relates to a compound of formula(I), (I-1), (I-2), (I-3), or (I-4), or a pharmaceutically acceptablesalt thereof, wherein m is 0-4 (i.e., m is 0, 1, 2, 3, or 4). In someembodiments, m is 0. In some embodiments, m is 1. In some embodiments, mis 2. In some embodiments, m is 3. In some embodiments, in is 4. In someembodiments, in is 0, 1, or 2. In some embodiments, m is 1 or 2.

In some embodiments, the disclosure relates to a compound of formula(I), (I-1), (I-2), (I-3), (I-4), (I-C), (I-C-1), (I-C-2), (I-C-3),(I-C-4), (I-C-a), (I-C-b), (I-C-c), (I-C-d), (I-C-e), (I-C-f), (I-M),(I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptablesalt thereof, wherein n is 0-4 (i.e., n is 0, 1, 2, 3, or 4). In someembodiments, n is 0. In some embodiments, n is 1. In some embodiments, nis 2. In some embodiments, n is 3. In some embodiments, n is 4. In someembodiments, n is 0, 1, or 2. In some embodiments, n is 1 or 2.

In some embodiments, the disclosure relates to a compound of formula(I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3),(I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-C), (I-C-1),(I-C-2), (I-C-3), (I-C-4), (I-C-a), (I-C-b), (I-C-c), (I-C-d), (I-C-e),(I-C-f), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1),(I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2),(I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof,wherein p is 0-4 (i.e., p is 0, 1, 2, 3, or 4). In some embodiments, pis 0. In some embodiments, p is 1. In some embodiments, p is 2. In someembodiments, p is 3. In some embodiments, p is 4. In some embodiments, pis 0, 1, or 2. In some embodiments, p is 1 or 2. In some embodiments, nandp are both 0. In some embodiments, m and n are both 0. In someembodiments, m and n are both 0. In some embodiments, m, n, andp are 0.In some embodiments, in and n are 0, and p is 1.

In some embodiments, the disclosure relates to a compound of formula(I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceuticallyacceptable salt thereof, wherein R^(a) and R^(b) form a C₁-C₄ alkylenegroup between the atoms to which they are attached, wherein said C₁-C₄alkylene group is substituted with 0-4 substituents selected from thegroup consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl. In someembodiments, R^(a) and Rb form a C₁-C₄ alkylene group between the atomsto which they are attached; and R^(c), R^(d), R^(e), R^(f), R^(g), andR^(h) are each hydrogen. In some embodiments, R^(a) and R^(b) form a C₁alkylene group between the atoms to which they are attached; and R^(c),R^(d), R^(e), R^(f), R^(g), and R^(h) are each hydrogen. In someembodiments, R^(a) and R^(b) form a C₂ alkylene group between the atomsto which they are attached; and R^(c), R^(d), R^(e), R^(f), R^(g), andR^(h) are each hydrogen. In some embodiments, R^(a) and R^(b) form a C₃alkylene group between the atoms to which they are attached; and R^(c),R^(d), R^(e), R^(f), R^(g), and R^(h) are each hydrogen. In someembodiments, R^(a) and R^(b) form a C₄ alkylene group between the atomsto which they are attached; and R^(c), R^(d), R^(e), R^(f), R^(g), andR^(h) are each hydrogen.

In some embodiments, the disclosure relates to a compound of formula(I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceuticallyacceptable salt thereof, wherein R^(a) and R^(e) form a C₁-C₂ alkylenegroup between the atoms to which they are attached, wherein said C₁-C₂alkylene group is substituted with 0-4 substituents selected from thegroup consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl. In someembodiments, R^(a) and R^(e) form a C₁-C₂ alkylene group between theatoms to which they are attached; and R^(b), R^(c), R^(d), R^(f), R^(g),and R^(h) are each hydrogen. In some embodiments, R^(a) and R^(e) form aC₁ alkylene group between the atoms to which they are attached; andR^(b), R^(c), R^(d), R^(f), R^(g), and R^(h) are each hydrogen. In someembodiments, R^(a) and R^(e) form a C₂ alkylene group between the atomsto which they are attached; and R^(b), R^(c), R^(d), R^(f), R^(g), andR^(h) are each hydrogen.

In some embodiments, the disclosure relates to a compound of formula(I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceuticallyacceptable salt thereof, wherein R^(a) and R^(g) form a C₁-C₃ alkylenegroup between the atoms to which they are attached, wherein said C₁-C₃alkylene group is substituted with 0-4 substituents selected from thegroup consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl. In someembodiments, R^(a) and R^(g) form a C₁-C₃ alkylene group between theatoms to which they are attached; and R^(b), R^(c), R^(d), R^(e), R^(f),and R^(h) are each hydrogen. In some embodiments, R^(a) and R^(g) form aC₁ alkylene group between the atoms to which they are attached; andR^(b), R^(c), R^(d), R^(e), R^(f), and R^(h) are each hydrogen. In someembodiments, R^(a) and R^(g) form a C₂ alkylene group between the atomsto which they are attached; and R^(b), R^(c), R^(d), R^(e), R^(f), andR^(h) are each hydrogen. In some embodiments, R^(a) and R^(g) form a C₃alkylene group between the atoms to which they are attached; and R^(b),R^(c), R^(d), R^(e), R^(f), and R^(h) are each hydrogen.

In some embodiments, the disclosure relates to a compound of formula(I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceuticallyacceptable salt thereof, wherein R^(b) and R^(c) form a C₁-C₄ alkylenegroup between the atoms to which they are attached, wherein said C₁-C₄alkylene group is substituted with 0-4 substituents selected from thegroup consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl. In someembodiments, R^(b) and R^(c) form a C₁-C₄ alkylene group between theatoms to which they are attached; and R^(a), R^(d), R^(e), R^(f), R^(g),and R^(h) are each hydrogen.

In some embodiments, R^(b) and R^(c) form a C₁-C₃ alkylene group betweenthe atoms to which they are attached; and R^(a), R^(d), R^(e), R^(f),R^(g), and R^(h) are each hydrogen. In some embodiments, R^(b) and R^(c)form a C₁ alkylene group between the atoms to which they are attached;and R^(a), R^(d), R^(e), R^(f), R^(g), and R^(h) are each hydrogen. Insome embodiments, R^(b) and R^(c) form a C₂ alkylene group between theatoms to which they are attached; and R^(a), R^(d), R^(e), R^(f), R^(g),and R^(h) are each hydrogen. In some embodiments, R^(b) and R^(c) form aC₃ alkylene group between the atoms to which they are attached; andR^(a), R^(d), R^(e), R^(f), R^(g), and R^(h) are each hydrogen. In someembodiments, R^(b) and R^(c) form a C₄ alkylene group between the atomsto which they are attached; and R^(a), R^(d), R^(e), R^(f), R^(g), andR^(h) are each hydrogen.

In some embodiments, the disclosure relates to a compound of formula(I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceuticallyacceptable salt thereof, wherein R^(b) and R^(e) form a C₁-C₃ alkylenegroup between the atoms to which they are attached, wherein said C₁-C₃alkylene group is substituted with 0-4 substituents selected from thegroup consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl. In someembodiments, R^(b) and R^(e) form a C₁-C₃ alkylene group between theatoms to which they are attached; and R^(a), R^(c), R^(d), R^(f), R^(g),and R^(h) are each hydrogen. In some embodiments, R^(b) and R^(e) form aC₁ alkylene group between the atoms to which they are attached; andR^(a), R^(c), R^(d), R^(f), R^(g), and R^(h) are each hydrogen. In someembodiments, R^(b) and R^(e) form a C₂ alkylene group between the atomsto which they are attached; and R^(a), R^(c), R^(d), R^(f), R^(g), andR^(h) are each hydrogen. In some embodiments, R^(b) and R^(e) form a C₃alkylene group between the atoms to which they are attached; and R^(a),R^(c), R^(d), R^(f), R^(g), and R^(h) are each hydrogen.

In some embodiments, the disclosure relates to a compound of formula(I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceuticallyacceptable salt thereof, wherein R^(b) and R^(g) form a C₁-C₄ alkylenegroup between the atoms to which they are attached, wherein said C₁-C₄alkylene group is substituted with 0-4 substituents selected from thegroup consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl. In someembodiments, R^(b) and R^(g) form a C₁-C₄ alkylene group between theatoms to which they are attached; and R^(a), R^(c), R^(d), R^(e), R^(f),and R^(h) are each hydrogen. In some embodiments, R^(b) and R^(g) form aC₁ alkylene group between the atoms to which they are attached; andR^(a), R^(c), R^(d), R^(e), R^(f), and R^(h) are each hydrogen. In someembodiments, R^(b) and R^(g) form a C₂ alkylene group between the atomsto which they are attached; and R^(a), R^(c), R^(d), R^(e), R^(f), andR^(h) are each hydrogen. In some embodiments, R^(b) and R^(g) form a C₃alkylene group between the atoms to which they are attached; and R^(a),R^(c), R^(d), R^(e), R^(f), and R^(h) are each hydrogen. In someembodiments, R^(b) and R^(g) form a C₄ alkylene group between the atomsto which they are attached; and R^(a), R^(c), R^(d), R^(e), R^(f), andR^(h) are each hydrogen.

In some embodiments, the disclosure relates to a compound of formula(I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceuticallyacceptable salt thereof, wherein R^(c) and R^(d) together with the atomto which they are attached, form a 3-6 membered cycloalkyl orheterocycloalkyl, wherein said 3-6 membered cycloalkyl orheterocycloalkyl is substituted with 0-4 substituents selected from thegroup consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl. In someembodiments, R^(c) and R^(d) together with the atom to which they areattached, form a 3-6 membered cycloalkyl or heterocycloalkyl; and R^(a),R^(b), R^(e), R^(f), R^(g), and R^(h) are each hydrogen. In someembodiments, R^(c) and R^(d) together with the atom to which they areattached, form a 3 membered cycloalkyl or a 4 membered heterocycloalkyl;and R^(a), R^(b), R^(e), R^(f), R^(g), and R^(h) are each hydrogen. Insome embodiments, R^(c) and R^(d) together with the atom to which theyare attached, form a 3-6 membered cycloalkyl; and R^(a), R^(b), R^(e),R^(f), R^(g), and R^(h) are each hydrogen. In some embodiments, R^(c)and R^(d) together with the atom to which they are attached, form a 3membered cycloalkyl; and R^(a), R^(b), R^(e), R^(f), R_(g) and R^(h) areeach hydrogen. In some embodiments, R^(c) and R^(d) together with theatom to which they are attached, form a 4 membered cycloalkyl; andR^(a), R^(b), R^(e), R^(f), R^(g), and R^(h) are each hydrogen. In someembodiments, R^(c) and R^(d) together with the atom to which they areattached, form a 5 membered cycloalkyl; and R^(a), R^(b), R^(e), R^(f),R^(g), and R^(h) are each hydrogen. In some embodiments, R^(c) and R^(d)together with the atom to which they are attached, form a 6 memberedcycloalkyl; and R^(a), R^(b), R^(e), R^(f), R^(g), and R^(h) are eachhydrogen. In some embodiments, R^(c) and R^(d) together with the atom towhich they are attached, form a 3-6 membered heterocycloalkyl ring; andR^(a), R^(b), R^(e), R^(f), R^(g), and R^(h) are each hydrogen. In someembodiments, R^(c) and R^(d) together with the atom to which they areattached, form a 3-6 membered heterocycloalkyl ring, wherein the 3-6membered heterocycloalkyl ring contains O, S, or NH; and R^(a), R^(b),R^(e), R^(f), R^(g), and R^(h) are each hydrogen. In some embodiments,R^(c) and R^(d) together with the atom to which they are attached, forma 3 membered heterocycloalkyl ring; and R^(a), R^(b), R^(e), R^(f),R^(g), and R^(h) are each hydrogen. In some embodiments, R^(c) and R^(d)together with the atom to which they are attached, form a 4 memberedheterocycloalkyl ring; and R^(a), R^(b), R^(e), R^(f), R^(g), and R^(h)are each hydrogen. In some embodiments, R^(c) and R^(d) together withthe atom to which they are attached, form an oxetane ring; and R^(a),R^(b), R^(e), R^(f), R^(g), and R^(h) are each hydrogen. In someembodiments, R^(c) and R^(d) together with the atom to which they areattached, form a 5 membered heterocycloalkyl ring; and R^(a), R^(b),R^(e), R^(f), R^(g), and R^(h) are each hydrogen. In some embodiments,R^(c) and R^(d) together with the atom to which they are attached, forma 6 membered heterocycloalkyl ring; and R^(a), R^(b), R^(e), R^(f),R^(g), and R^(h) are each hydrogen. In some embodiments, R^(c) and R^(d)together form ═O. In some embodiments, R^(c) and R^(d) together form ═O;and R^(a), R^(b), R^(e), R^(f), R^(g), and R^(h) are each hydrogen.

In some embodiments, the disclosure relates to a compound of formula(I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceuticallyacceptable salt thereof, wherein R^(c) and R^(e) form a C₁-C₄ alkylenegroup between the atoms to which they are attached, wherein said C₁-C₄alkylene group is substituted with 0-4 substituents selected from thegroup consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl. In someembodiments, R^(c) and R^(e) form a C₁-C₄ alkylene group between theatoms to which they are attached; and R^(a), R^(b), R^(d), R^(f), R^(g),and R^(h) are each hydrogen. In some embodiments, R^(c) and R^(e) form aC₁ alkylene group between the atoms to which they are attached; andR^(a), R^(b), R^(d), R^(f), R^(g), and R^(h) are each hydrogen. In someembodiments, R^(c) and R^(e) form a C₂ alkylene group between the atomsto which they are attached; and R^(a), R^(b), R^(d), R^(f), R^(g), andR^(h) are each hydrogen. In some embodiments, R^(c) and R^(e) form a C₃alkylene group between the atoms to which they are attached; and R^(a),R^(b), R^(d), R^(f), R^(g), and R^(h) are each hydrogen. In someembodiments, R^(c) and R^(e) form a C₄ alkylene group between the atomsto which they are attached; and R^(a), R^(b), R^(d), R^(f), R^(g), andR^(h) are each hydrogen.

In some embodiments, the disclosure relates to a compound of formula(I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceuticallyacceptable salt thereof, wherein R^(c) and R^(g) form a C₁-C₃ alkylenegroup between the atoms to which they are attached, wherein said C₁-C₃alkylene group is substituted with 0-4 substituents selected from thegroup consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl. In someembodiments, R^(c) and R^(g) form a C₁-C₃ alkylene group between theatoms to which they are attached; and R^(a), R^(b), R^(d), R^(e), R^(f),and R^(h) are each hydrogen. In some embodiments, R^(c) and R^(g) form aC₁-C₂ alkylene group between the atoms to which they are attached; andR^(a), R^(b), R^(d), R^(e), R^(f), and R^(h) are each hydrogen. In someembodiments, R^(c) and R^(g) form a C₁ alkylene group between the atomsto which they are attached; and R^(a), R^(b), R^(d), R^(e), R^(f), andR^(h) are each hydrogen. In some embodiments, R^(c) and R^(g) form a C₂alkylene group between the atoms to which they are attached; and R^(a),R^(b), R^(d), R^(e), R^(f), and R^(h) are each hydrogen. In someembodiments, R^(c) and R^(g) form a C₃ alkylene group between the atomsto which they are attached; and R^(a), R^(b), R^(d), R^(e), R^(f), andR^(h) are each hydrogen.

In some embodiments, the disclosure relates to a compound of formula(I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceuticallyacceptable salt thereof, wherein R^(e) and R^(f) together with the atomto which they are attached, form a 3-6 membered cycloalkyl orheterocycloalkyl, wherein said 3-6 membered cycloalkyl orheterocycloalkyl is substituted with 0-4 substituents selected from thegroup consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl. In someembodiments, R^(c) and R^(f) together with the atom to which they areattached, form a 3-6 membered cycloalkyl or heterocycloalkyl; and R^(a),R^(b), R^(c), R^(d), R^(g), and R^(h) are each hydrogen. In someembodiments, R^(e) and R^(f) together with the atom to which they areattached, form a 3-6 membered cycloalkyl; and R^(a), R^(b), R^(c),R^(d), R^(g), and R^(h) are each hydrogen. In some embodiments, R^(e)and R^(f) together with the atom to which they are attached, form a 3membered cycloalkyl; and R^(a), R^(b), R^(c), R^(d), R^(g), and R^(h)are each hydrogen. In some embodiments, R^(e) and R^(f) together withthe atom to which they are attached, form a 4 membered cycloalkyl; andR^(a), R^(b), R^(e), R^(d), R^(g), and R^(h) are each hydrogen. In someembodiments, R^(e) and R^(f) together with the atom to which they areattached, form a 5 membered cycloalkyl; and R^(a), R^(b), R^(c), R^(d),R^(g), and R^(h) are each hydrogen. In some embodiments, R^(e) and R^(f)together with the atom to which they are attached, form a 6 memberedcycloalkyl; and R^(a), R^(b), R^(c), R^(d), R^(g), and R^(h) are eachhydrogen. In some embodiments, R^(e) and R^(f) together with the atom towhich they are attached, form a 3-6 membered heterocycloalkyl ring; andR^(a), R^(b), R^(c), R^(d), R^(g), and R^(h) are each hydrogen. In someembodiments, R^(e) and R^(f) together with the atom to which they areattached, form a 3-6 membered heterocycloalkyl ring, wherein the 3-6membered heterocycloalkyl ring contains O, S, or NH; and R^(a), R^(b),R^(c), R^(d), R^(g), and R^(h) are each hydrogen. In some embodiments,R^(e) and R^(f) together with the atom to which they are attached, forma 3 membered heterocycloalkyl ring; and R^(a), R^(b), R^(c), R^(d),R^(g), and R^(h) are each hydrogen. In some embodiments, R^(e) and R^(f)together with the atom to which they are attached, form a 4 memberedheterocycloalkyl ring; and R^(a), R^(b), R^(c), R^(d), R^(g), and R^(h)are each hydrogen. In some embodiments, R^(e) and R^(f) together withthe atom to which they are attached, form an oxetane ring; and R^(a),R^(b), R^(c), R^(d), R^(g), and R^(h) are each hydrogen. In someembodiments, R^(e) and R^(f) together with the atom to which they areattached, form a 5 membered heterocycloalkyl ring; and R^(a), R^(b),R^(c), R^(d), R^(g), and R^(h) are each hydrogen. In some embodiments,R^(e) and R^(f) together with the atom to which they are attached, forma 6 membered heterocycloalkyl ring; and R^(a), R^(b), R^(c), R^(d),R^(g), and R^(h) are each hydrogen. In some embodiments, R^(e) and R^(f)together form ═O. In some embodiments, R^(e) and R^(f) together form ═O;and R^(a), R^(b), R^(c), R^(d), R^(g), and R^(h) are each hydrogen.

In some embodiments, the disclosure relates to a compound of formula(I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceuticallyacceptable salt thereof, wherein R^(e) and R^(g) form a C₁-C₃ alkylenegroup between the atoms to which they are attached, wherein said C₁-C₃alkylene group is substituted with 0-4 substituents selected from thegroup consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl. In someembodiments, R^(e) and R^(g) form a C₁-C₃ alkylene group between theatoms to which they are attached; and R^(a), R^(b), R^(c), R^(d), R^(f),and R^(h) are each hydrogen. In some embodiments, R^(e) and R^(g) form aC₁ alkylene group between the atoms to which they are attached; andR^(a), R^(b), R^(c), R^(d), R^(f), and R^(h) are each hydrogen. In someembodiments, R^(e) and R^(g) form a C₂ alkylene group between the atomsto which they are attached; and R^(a), R^(b), R^(c), R^(d), R^(f), andR^(h) are each hydrogen. In some embodiments, R^(e) and R^(g) form a C₃alkylene group between the atoms to which they are attached; and R^(a),R^(b), R^(c), R^(d), R^(f), and R^(h) are each hydrogen.

In some embodiments, the disclosure relates to a compound of formula(I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceuticallyacceptable salt thereof, wherein R^(g) and R^(h) together with the atomto which they are attached, form a 3-6 membered cycloalkyl orheterocycloalkyl, wherein said 3-6 membered cycloalkyl orheterocycloalkyl is substituted with 0-4 substituents selected from thegroup consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl. In someembodiments, R^(g) and R^(h) together with the atom to which they areattached, form a 3-6 membered cycloalkyl or heterocycloalkyl; and R^(a),R^(b), R^(c), R^(d), R^(e), and R^(f) are each hydrogen. In someembodiments, R^(g) and R^(h) together with the atom to which they areattached, form a 3-6 membered cycloalkyl; and R^(a), R^(b), R^(c),R^(d), R^(e), and R^(f) are each hydrogen. In some embodiments, R^(g)and R^(h) together with the atom to which they are attached, form a 3membered cycloalkyl; and R^(a), R^(b), R^(c), R^(d), R^(e), and R^(f)are each hydrogen. In some embodiments, R^(g) and R^(h) together withthe atom to which they are attached, form a 4 membered cycloalkyl; andR^(a), R^(b), R^(c), R^(d), R^(e), and R^(f) are each hydrogen. In someembodiments, R^(g) and R^(h) together with the atom to which they areattached, form a 5 membered cycloalkyl; and R^(a), R^(b), R^(c), R^(d),R^(e), and R^(f) are each hydrogen. In some embodiments, R^(g) and R^(h)together with the atom to which they are attached, form a 6 memberedcycloalkyl; and R^(a), R^(b), R^(c), R^(d), R^(e), and R^(f) are eachhydrogen. In some embodiments, R^(g) and R^(h) together with the atom towhich they are attached, form a 3-6 membered heterocycloalkyl ring; andR^(a), R^(b), R^(e), R^(d), R^(e), and R^(f) are each hydrogen. In someembodiments, R^(g) and R^(h) together with the atom to which they areattached, form a 3-6 membered heterocycloalkyl ring, wherein the 3-6membered heterocycloalkyl ring contains O, S, or NH; and R^(a), R^(b),R^(c), R^(d), R^(e), and R^(f) are each hydrogen. In some embodiments,R^(g) and R^(h) together with the atom to which they are attached, forma 3 membered heterocycloalkyl ring; and R^(a), R^(b), R^(e), R^(d),R^(e), and R^(f) are each hydrogen. In some embodiments, R^(g) and R^(h)together with the atom to which they are attached, form a 4 memberedheterocycloalkyl ring; and R^(a), R^(b), R^(c), R^(d), R^(e), and R^(f)are each hydrogen. In some embodiments, R^(g) and R^(h) together withthe atom to which they are attached, form an oxetane ring; and R^(a),R^(b), R^(c), R^(d), R^(e), and R^(f) are each hydrogen. In someembodiments, R^(g) and R^(h) together with the atom to which they areattached, form a 5 membered heterocycloalkyl ring; and R^(a), R^(b),R^(c), R^(d), R^(e), and R^(f) are each hydrogen. In some embodiments,R^(g) and R^(h) together with the atom to which they are attached, forma 6 membered heterocycloalkyl ring; and R^(a), R^(b), R^(c), R^(d),R^(e), and R^(f) are each hydrogen. In some embodiments, R^(g) and R^(h)together form ═O. In some embodiments, R^(g) and R^(h) together form ═O;and R^(a), R^(b), R^(c), R^(d), R^(e), and R^(f) are each hydrogen.

In some embodiments, the disclosure relates to a compound of formula(I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceuticallyacceptable salt thereof, wherein R^(a), R^(b), R^(c), R^(d), R^(e),R^(f), R^(g), and R^(h) are defined as follows:

(ii) R^(a) and R^(e) form a C₁-C₂ alkylene group between the atoms towhich they are attached, wherein said C₁-C₂ alkylene group issubstituted with 0-4 substituents selected from the group consisting ofhalogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and R^(b), R^(c), R^(d),R^(f), R^(g), and R^(h) are each independently hydrogen, halogen, C₁-C₃alkyl, or C₁-C₃ haloalkyl; or

(iv) R^(b) and R^(c) form a C₁-C₄ alkylene group between the atoms towhich they are attached, wherein said C₁-C₄ alkylene group issubstituted with 0-4 substituents selected from the group consisting ofhalogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and R^(a), R^(d), R^(e),R^(f), R^(g), and R^(h) are each independently hydrogen, halogen, C₁-C₃alkyl, or C₁-C₃ haloalkyl; or

(vii) R^(c) and R^(d) together with the atom to which they are attached,form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6membered cycloalkyl or heterocycloalkyl is substituted with 0-4substituents selected from the group consisting of halogen, C₁-C₃ alkyl,and C₁-C₃ haloalkyl; and R^(a), R^(b), R^(e), R^(f), R^(g), and R^(h)are each independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃haloalkyl; or

(viii) Re and R^(d) together form ═O; and R^(a), R^(b), R^(e), R^(f),R^(g), and R^(h) are each independently hydrogen, halogen, C₁-C₃ alkyl,or C₁-C₃ haloalkyl; or

(ix) R^(c) and R^(e) form a C₁-C₄ alkylene group between the atoms towhich they are attached, wherein said C₁-C₄ alkylene group issubstituted with 0-4 substituents selected from the group consisting ofhalogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl, and R^(a), R^(b), R^(d),R^(f), R^(g), and R^(h) are each independently hydrogen, halogen, C₁-C₃alkyl, or C₁-C₃ haloalkyl; or

(x) R^(c) and R^(g) form a C₁-C₃ alkylene group between the atoms towhich they are attached, wherein said C₁-C₃ alkylene group issubstituted with 0-4 substituents selected from the group consisting ofhalogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl, and R^(a), R^(b), R^(d),R^(e), R^(f), and R^(h) are each independently hydrogen, halogen, C₁-C₃alkyl, or C₁-C₃ haloalkyl; or

(xi) R^(e) and R^(f) together with the atom to which they are attached,form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6membered cycloalkyl or heterocycloalkyl is substituted with 0-4substituents selected from the group consisting of halogen, C₁-C₃ alkyl,and C₁-C₃ haloalkyl; and R^(a), R^(b), R^(c), R^(d), R^(g), and R^(h)are each independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃haloalkyl; or

(xiii) R^(c) and R^(g) form a C₁-C₃ alkylene group between the atoms towhich they are attached, wherein said C₁-C₃ alkylene group issubstituted with 0-4 substituents selected from the group consisting ofhalogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and R^(a), R^(b), R^(c),R^(d), R^(f), and R^(h) are each independently hydrogen, halogen, C₁-C₃alkyl, or C₁-C₃ haloalkyl; or

(xv) R^(g) and R^(h) together form ═O; and R^(a), R^(b), R^(c), R^(d),R^(e), and R^(f) are each independently hydrogen, halogen, C₁-C₃ alkyl,or C₁-C₃ haloalkyl.

In some embodiments, the disclosure relates to a compound of formula(I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceuticallyacceptable salt thereof, wherein R^(a), R^(b), R^(c), R^(d), R^(e),R^(f), R^(g), and R^(h) are defined as follows:

(ii) R^(a) and R^(e) form a C₁-C₂ alkylene group between the atoms towhich they are attached; and R^(b), R^(c), R^(d), R^(f), R^(g), andR^(h) are each hydrogen; or

(iv) R^(b) and R^(c) form a C₁-C₄ alkylene group between the atoms towhich they are attached; and R^(a), R^(d), R^(e), R^(f), R^(g), andR^(h) are each hydrogen; or

(vii) R^(c) and R^(d) together with the atom to which they are attached,form a 3-6 membered cycloalkyl or heterocycloalkyl; and R^(a), R^(b),R^(e), R^(f), R^(g), and R^(h) are each hydrogen; or

(viii) R^(c) and R^(d) together form ═O; and R^(a), R^(b), R^(e), R^(f),R^(g), and R^(h) are each hydrogen; or

(ix) R^(c) and R^(e) form a C₁-C₄ alkylene group between the atoms towhich they are attached; and R^(a), R^(b), R^(d), R^(f), R^(g), andR^(h) are each hydrogen; or

(x) R^(c) and R^(g) form a C₁-C₃ alkylene group between the atoms towhich they are attached; and R^(a), R^(b), R^(d), R^(e), R^(f), andR^(h) are each hydrogen; or

(xi) R^(e) and R^(f) together with the atom to which they are attached,form a 3-6 membered cycloalkyl or heterocycloalkyl; and R^(a), R^(b),R^(c), R^(d), R^(g), and R^(h) are each hydrogen; or

(xiii) R^(e) and R^(g) form a C₁-C₃ alkylene group between the atoms towhich they are attached; and R^(a), R^(b), R^(c), R^(d), R^(f), andR^(h) are each independently hydrogen; or

(xv) R^(g) and R^(h) together form ═O; and R^(a), R^(b), R^(c), R^(d),R^(e), and R^(f) are each hydrogen.

In some embodiments, the disclosure relates to a compound of formula(I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceuticallyacceptable salt thereof, wherein R^(a), R^(b), R^(c), R^(d), R^(e),R^(f), R^(g), and R^(h) are defined as follows:

(ii) R^(a) and R^(e) form a C₁-C₂ alkylene group between the atoms towhich they are attached; and R^(b), R^(c), R^(d), R^(f), R^(g), andR^(h) are each hydrogen; or

(iv) R^(b) and R^(c) form a C₁-C₃ alkylene group between the atoms towhich they are attached, and R^(a), R^(d), R^(e), R^(f), R_(g) and R^(h)are each hydrogen; or

(vii) R^(c) and R^(d) together with the atom to which they are attached,form a 3-membered cycloalkyl or a 4-membered heterocycloalkyl; andR^(a), R^(b), R^(e), R^(f), R^(g), and R^(h) are each hydrogen; or

(viii) R^(c) and R^(d) together form ═O; and R^(a), R^(b), R^(e), R^(f),R^(g), and R^(h) are each hydrogen; or

(ix) R^(c) and R^(e) form a C₁ alkylene group between the atoms to whichthey are attached; and R^(a), R^(b), R^(d), R^(f), R^(g), and R^(h) areeach hydrogen; or

(x) R^(c) and R^(g) form a C₁-C₂ alkylene group between the atoms towhich they are attached; and R^(a), R^(b), R^(d), R^(e), R^(f), andR^(h) are each hydrogen; or

(xi) R^(e) and R^(f) together with the atom to which they are attached,form a 4-membered heterocycloalkyl; and R^(a), R^(b), R^(c), R^(d),R^(g), and R^(h) are each hydrogen; or

(xiii) R^(e) and R^(g) form a C₂ alkylene group between the atoms towhich they are attached; and R^(a), R^(b), R^(c), R^(d), R^(f), andR^(h) are each independently hydrogen; or

(xv) R^(g) and R^(h) together form ═O; and R^(a), R^(b), R^(c), R^(d),R^(e), and R^(f) are each hydrogen.

In some embodiments, the disclosure relates to a compound of formula(I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceuticallyacceptable salt thereof, wherein R^(a), R^(b), R^(c), R^(d), R^(e),R^(f), R^(g), and R^(h) are defined as follows:

(ii) R^(a) and R^(e) form a C₁-C₂ alkylene group between the atoms towhich they are attached; and R^(b), R^(c), R^(d), R^(f), and R^(g) areeach hydrogen; or

(iv) R^(b) and R^(c) form a C₁-C₂ alkylene group between the atoms towhich they are attached; and R^(a), R^(c), R^(d), R^(f), and R^(g) areeach hydrogen; or

(vii) R^(c) and R^(d) together with the atom to which they are attached,form a 3 membered cycloalkyl; and R^(a), R^(b), R^(e), R^(f), and R^(g)are each hydrogen; or

(x) R^(c) and R^(g) form a C₁-C₂ alkylene group between the atoms towhich they are attached; and R^(a), R^(b), R^(d), R^(e), and R^(g) areeach hydrogen; or

(xi) R^(e) and R^(f) together with the atom to which they are attached,form a 4 membered heterocycloalkyl; and R^(a), R^(b), R^(c), R^(d), andR^(g) are each hydrogen; or

(xiii) R^(e) and R^(g) form a C₂ alkylene group between the atoms towhich they are attached; and R^(a), R^(b), R^(c), R^(d), and R^(f) areeach independently hydrogen.

In some embodiments, the disclosure relates to a compound of formula(I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceuticallyacceptable salt thereof, wherein

is selected from:

In some embodiments,

In some embodiments.

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2),(I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2),(I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1),(I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable saltthereof, wherein X¹ is C or N. In some embodiments, X¹ is C. In someembodiments, X¹ is N.

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2),(I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2),(I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1),(I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable saltthereof, wherein X² is CH, CR¹, O, S, N, NH, or NR¹, as valency permits.In some embodiments, X² is CH. In some embodiments, X² is CR¹. In someembodiments, X² is O. In some embodiments, X² is S. In some embodiments,X² is N. In some embodiments, X² is NH. In some embodiments, X² is NR¹.

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2),(I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2),(I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1),(I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable saltthereof, wherein X³ is CH, CR¹, O, S, N, NH, or NR¹, as valency permits.In some embodiments, X³ is CH. In some embodiments, X³ is CR¹. In someembodiments, X³ is O. In some embodiments, X³ is S. In some embodiments,X³ is N. In some embodiments, X³ is NH. In some embodiments, X³ is NR¹.

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2),(I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2),(I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1),(I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable saltthereof, wherein X⁴ is C or N. In some embodiments, X⁴ is C. In someembodiments, X⁴ is N.

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1),(I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1),(I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or apharmaceutically acceptable salt thereof, wherein X⁵ is a bond, CH, CR¹,O, S, N, NH, or NR¹, as valency permits. In some embodiments, X⁵ is abond. In some embodiments, X⁵ is CH. In some embodiments, X⁵ is CR¹. Insome embodiments, X⁵ is O. In some embodiments, X⁵ is S. In someembodiments, X⁵ is N. In some embodiments, X⁵ is NH. In someembodiments, X⁵ is NR¹.

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2),(I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2),(I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1),(I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable saltthereof, wherein X⁶ is CH, CR¹, O, S, N, NH, or NR¹, as valency permits.In some embodiments, X⁶ is CH. In some embodiments, X⁶ is CR¹. In someembodiments, X⁶ is O. In some embodiments, X⁶ is S. In some embodiments,X⁶ is N. In some embodiments, X⁶ is NH. In some embodiments, X⁶ is NR¹.

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1),(I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1),(I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or apharmaceutically acceptable salt thereof, wherein X¹ is C; X² is N; X³is NH; X⁴ is C; X⁵ is a bond; and X⁶ is CH.

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1),(I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1),(I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or apharmaceutically acceptable salt thereof, wherein X¹ is C; X² is N; X³is CH; X⁴ is C; X⁵ is a bond; and X⁶ is S.

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1),(I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1),(I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or apharmaceutically acceptable salt thereof, wherein X¹ is C; X² is CH; X³is CH; X⁴ is C; X⁵ is CH; and X⁶ is C.

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1),(I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1),or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y¹ isC or N. In some embodiments, Y¹ is C. In some embodiments, Y¹ is N.

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1),(I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1),or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y² isC or N. In some embodiments, Y² is C. In some embodiments, Y² is N.

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2),(I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2),(I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or apharmaceutically acceptable salt thereof, wherein Y³ is CH, CR², O, S,N, NH, or NR², as valency permits. In some embodiments, Y³ is CH. Insome embodiments, Y³ is CR². In some embodiments, Y³ is O. In someembodiments, Y³ is S. In some embodiments, Y³ is N. In some embodiments,Y³ is NH. In some embodiments, Y³ is NR².

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2),(I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2),(I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or apharmaceutically acceptable salt thereof, wherein Y⁴ is a bond, CH, CR²,O, S, N, NH, or NR², as valency permits. In some embodiments, Y⁴ is abond. In some embodiments, Y⁴ is CH. In some embodiments, Y⁴ is CR². Insome embodiments, Y⁴ is O. In some embodiments, Y⁴ is S. In someembodiments, Y⁴ is N. In some embodiments, Y⁴ is NH. In someembodiments, Y⁴ is NR².

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2),(I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2),(I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or apharmaceutically acceptable salt thereof, wherein Y⁵ is CH, CR², O, S,N, NH, or NR², as valency permits. In some embodiments, Y⁵ is CH. Insome embodiments, Y⁵ is CR². In some embodiments, Y⁵ is O. In someembodiments, Y⁵ is S. In some embodiments, Y⁵ is N. In some embodiments,Y⁵ is NH. In some embodiments, Y⁵ is NR².

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2),(I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2),(I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or apharmaceutically acceptable salt thereof, wherein Y⁶ is CH, CR², O, S,N, NH, or NR², as valency permits. In some embodiments, Y⁶ is CH. Insome embodiments, Y⁶ is CR². In some embodiments, Y⁶ is O. In someembodiments, Y⁶ is S. In some embodiments, Y⁶ is N. In some embodiments,Y⁶ is NH. In some embodiments, Y⁶ is NR².

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1),(I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1),or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y¹ isC; Y² is C; Y³ is CH; Y⁴ is CH; Y⁵ is CH; and Y⁶ is CH.

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1),(I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1),or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y¹ isC; Y² is C; Y³ is CR²; Y⁴ is CH; Y⁵ is CH; and Y⁶ is CH.

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1),(I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1),or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y¹ isC; Y² is C; Y³ is CH; Y⁴ is CR²; Y⁵ is CH; and Y⁶ is CH.

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1),(I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1),or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y¹ isC; Y² is C; Y³ is CH; Y⁴ is CH; Y⁵ is CR²; and Y⁶ is CH.

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1),(I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1),or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y¹ isC; Y² is C; Y³ is N; Y⁴ is CH; Y⁵ is CH; and Y⁶ is CR². In someembodiments, the disclosure relates to a compound of formula (I-A), or apharmaceutically acceptable salt thereof, wherein Y¹ is C; Y² is C; Y³is N; Y⁴ is CH; Y⁵ is CH; and Y⁶ is CH.

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1),(I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1),or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y¹ isC; Y² is C; Y³ is CH; Y⁴ is N; Y⁵ is CH; and Y⁶ is CH.

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1),(I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1),or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y¹ isC; Y² is C; Y³ is CH; Y⁴ is CH; Y⁵ is N; and Y⁶ is CH.

In some embodiments, the disclosure relates to a compound of formula(I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1),(I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1),or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y¹ isC; Y² is C; Y³ is CH; Y⁴ is CH; Y⁵ is CH; and Y⁶ is N.

In some embodiments, the disclosure relates to a compound of formula(I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B-1), (I-B-2), (I-B-3), (I-B-4),(I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-M-1), (I-M-2), (I-M-3), or(I-M-4), or a pharmaceutically acceptable salt thereof, wherein R^(j),R^(k), R^(m), R^(n), R^(o), R^(p), R^(q), and R^(r), when present, areeach independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.In some embodiments, R^(j), R^(k), R^(m), R^(n), R^(o), R^(p), R^(q),and R^(r), when present, are each hydrogen.

In some embodiments, the disclosure relates to a compound of formula(I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceuticallyacceptable salt thereof, wherein X¹ is C; X² is N; X³ is NH; X⁴ is C;and X⁶ is CH.

In some embodiments, the disclosure relates to a compound of formula(I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceuticallyacceptable salt thereof, wherein X¹ is C; X² is N; X³ is CH; X⁴ is C;and X⁶ is S.

In some embodiments, the disclosure relates to a compound of formula(I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceuticallyacceptable salt thereof, wherein Y³ is CH; Y⁴ is CH; Y⁵ is CH; and Y⁶ isCH.

In some embodiments, the disclosure relates to a compound of formula(I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceuticallyacceptable salt thereof, wherein Y³ is CR²; Y⁴ is CH; Y⁵ is CH; and Y⁶is CH.

In some embodiments, the disclosure relates to a compound of formula(I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceuticallyacceptable salt thereof, wherein Y³ is CH; Y⁴ is CR²; Y⁵ is CH; and Y⁶is CH.

In some embodiments, the disclosure relates to a compound of formula(I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceuticallyacceptable salt thereof, wherein Y³ is CH; Y⁴ is CH; Y⁵ is CR²; and Y⁶is CH

In some embodiments, the disclosure relates to a compound of formula(I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceuticallyacceptable salt thereof, wherein Y³ is CH; Y⁴ is CH; Y⁵ is CH; and Y⁶ isCR².

In some embodiments, the disclosure relates to a compound of formula(I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceuticallyacceptable salt thereof, wherein Y³ is N; Y⁴ is CH; Y⁵ is CH; and Y⁶ isCH.

In some embodiments, the disclosure relates to a compound of formula(I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceuticallyacceptable salt thereof, wherein Y³ is CH; Y⁴ is N; Y⁵ is CH, and Y⁶ isCH.

In some embodiments, the disclosure relates to a compound of formula(I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceuticallyacceptable salt thereof, wherein Y³ is CH; Y⁴ is CH; Y⁵ is N, and Y⁶ isCH.

In some embodiments, the disclosure relates to a compound of formula(I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceuticallyacceptable salt thereof, wherein Y³ is CH; Y⁴ is CH; Y⁵ is CH; and Y⁶ isN.

In some embodiments, the disclosure relates to a compound providedherein, or a pharmaceutically acceptable salt thereof, that is a USP30Inhibitor Compound having an IC50 value of ≤1 μM and >0.001 μM asmeasured in a Ubiquitin-Rhodamine 110 Assay as described in Example 1.

In another aspect, the disclosure relates to a compound selected fromTable 1, or a pharmaceutically acceptable salt thereof. Each pair ofcompounds listed in Table 1 (i.e., compounds 1-a and 1-b, compounds 2-aand 2-b, etc.) was obtained as a racemic mixture, and were thenseparated by chiral HPLC according to the procedure described in Example2, Step 7, or a similar method, to obtain the individual compounds insubstantially enantiomerically pure form. For each pair of compounds,the first compound (i.e., compounds 1-a, 2-a, etc.) was the firsteluting isomer, and the second compound (i.e., compounds 1-b, 2-b, etc.)was the second eluting isomer. The stereochemical descriptors reflectthe relative stereochemistry of each compound. The absolutestereochemistry of each compound was arbitrarily assigned. In someembodiments, the compound selected from Table 1, or a pharmaceuticallyacceptable salt thereof, is present in a racemic mixture. In someembodiments, the compound selected from Table 1, or a pharmaceuticallyacceptable salt thereof, is present in substantially enantiomericallypure form.

TABLE 1 Compounds of the Disclosure Compound Number Compound Structureand Chemical Name  1-a

 1-b

 2-a

 2-b

 3-a

 3-b

 4-a

 4-b

 5-a

 5-b

 6-a

 6-b

 7-a

 7-b

 8-a

 8-b

 9-a

 9-b

13-a

13-b

20-a

20-b

In another aspect, the disclosure relates to a compound selected fromTable 2, or a pharmaceutically acceptable salt thereof. In someembodiments, the compound, or a pharmaceutically acceptable saltthereof, is present in a racemic mixture with its enantiomer. In someembodiments, the compound, or a pharmaceutically acceptable saltthereof, is present in substantially enantiomerically pure form.

In another aspect, the disclosure relates to the enantiomer of acompound selected from Table 2, or a pharmaceutically acceptable saltthereof. In some embodiments, the enantiomer, or a pharmaceuticallyacceptable salt thereof, is present in a racemic mixture. In someembodiments, the enantiomer, or a pharmaceutically acceptable saltthereof, is present in substantially enantiomerically pure form.

TABLE 2 Compounds of the Disclosure Compound Number Compound Structureand Chemical Name  10

 11

 12

 13

 14

 15

 16

 17

 18

 19

 20

 21

 22

 23

 24

 25

 26

 27

 28

 29

 30

 31

 32

 33

 34

 35

 36

 37

 38

 39

 40

 41

 42

 43

 44

 45

 46

 47

 48

 49

 50

 51

 52

 53

 54

 55

 56

 57

 58

 59

 60

 61

 62

 63

 64

 65

 66

 67

 68

 69

 70

 71

 72

 73

 74

 75

 76

 77

 78

 79

 80

 81

 82

 83

 84

 85

 86

 87

 88

 89

 90

 91

 92

 93

 94

 95

 96

 97

 98

 99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

In some embodiments, a compound described herein is provided in non-saltform. In some embodiments, a compound described herein is provided as apharmaceutically acceptable salt.

In another aspect, the disclosure relates to a compound, or apharmaceutically acceptable salt thereof, prepared by a methodcomprising: preparing a compound of the present disclosure as a mixtureof stereoisomers; separating the stereoisomers by chiral HPLC accordingto the procedure described in Example 2, Step 7; isolating one or morestereoisomers that are USP30 Inhibitor Compounds having an IC₅₀ value of<1 μM as measured in a Ubiquitin-Rhodamine 110 Assay as described inExample 1; and optionally treating the isolated stereoisomer with anacid or base to afford a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is the 1^(st) eluting isomer. In someembodiments, the compound is the 2^(nd) eluting isomer. In someembodiments, the compound is the 3^(rd) eluting isomer. In someembodiments, the compound is the 4^(th) eluting isomer. In someembodiments, the compound is the 5^(th), 6^(th), 7^(th), or 8^(th)eluting isomer.

In some embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is a USP30 Inhibitor Compoundhaving an IC₅₀ value of ≤1 μM as measured in a Ubiquitin-Rhodamine 110Assay as described in Example 1. In some embodiments, the IC₅₀ value is≤0.1 μM.

Pharmaceutical Compositions and Routes of Administration

The disclosure also relates to a pharmaceutical composition comprisingone or more compounds provided herein, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier. In someembdiments, the pharmaceutical composition comprises a therapeuticallyeffective amount of the one or more compounds, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the pharmaceuticalcomposition is for use in a method of treating a neurodegenerativedisorder, such as Parkinson's Disease.

The compounds and pharmaceutically acceptable salts disclosed herein maybe administered via any mode of administration for therapeutic agents,consistent with conventional pharmaceutical practices. In someembodiments, the pharmaceutical compositions reported herein can beprovided in a unit dosage form. In some embodiments, the pharmaceuticalcompositions reported herein can be provided in an oral dosage form. Insome embodiments, the pharmaceutical compositions described herein canbe provided in a solid oral dosage form, such as a tablet, capsule,powder, or cachet.

The pharmaceutical compositions described herein can be preparedaccording to conventional mixing, granulating or coating methods. Forexample, oral dosage forms (e.g., tablets) may be prepared by dryblending or dry granulation. The pharmaceutical compositions describedherein can contain from about 0.1% to about 99%, from about 5% to about90%, or from about 1% to about 20% of the compound or pharmaceuticallyacceptable salt by weight or volume. The pharmaceutically acceptablecarriers employed in the pharmaceutical compositions described hereinmay include one or more pharmaceutical excipients, such as fillers,disintegrants, lubricants, glidants, anti-adherents, anti-statics,surfactants, or stabilizing additives. Suitable solid carriers are knownin the art, e.g., magnesium carbonate, magnesium stearate, talc, sugaror lactose. With some drugs, the presence of such additives promotes thestability and dispersibility of the agent in solution. Suitable, butnon-limiting, examples of stabilizing additives include gum acacia,gelatin, methyl cellulose, polyethylene glycol, carboxylic acids andsalts thereof, and polylysine. In some embodiments, the stabilizingadditives are gum acacia, gelatin and methyl cellulose. Examples ofpharmaceutically acceptable carriers and methods of manufacture forvarious compositions may be found in A. Gennaro (ed.), Remington'sPharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co.,Easton, Pa.

The pharmaceutical compositions described herein may contain thecompound or pharmaceutically acceptable salt in substantially pure form,such as at least 60% pure, more suitably at least 75% pure, preferablyat least 85% pure and most preferably at least 98% pure (w/w).

The compounds and pharmaceutically acceptable salts described herein arepreferably administered in a therapeutically effective amount (e.g., anamount having a suitable favorable therapeutic index). The amount andfrequency of administration will be regulated according to the judgmentof the attending clinician considering such factors as the age, gender,condition and size of the patient, as well as severity of the medicalcondition being treated; the route of administration; the renal orhepatic function of the patient; and the particular compound orpharmaceutically acceptable salt employed. A physician or veterinarianof ordinary skill in the art can readily determine and prescribe theeffective amount of the drug required to prevent, counter or arrest theprogress of the condition. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

Uses of Compounds Disclosed Herein

The present disclosure also provides uses of compounds of formula (I).Compounds of formula (I) are useful in medicine. For examples, compoundsand compositions described herein are inhibitors of USP30. Withoutwishing to be bound by any particular theory, such inhibition of USP30can provide treatment of the symptoms and/or underlying causes ofdiseases or conditions associated with USP30 activity. In someembodiments, inhibitors of USP30 can be used to treat neurodegenerativeand neurologic diseases or conditions, such as Parkinson's disease.

Provided herein are methods of treating a disease or disorder associatedwith a ubiquitin-specific protease (e.g., USP30), comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound or composition provided herein. In someembodiments, the disease or disorder associated with aubiquitin-specific protease (e.g., USP30) is a neurodegenerative diseaseor disorder (e.g., Parkinson's disease).

The present disclosure also provides methods of inhibiting aubiquitin-specific protease (e.g., USP30) in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound or composition provided herein.

The present disclosure also provides methods of treating aneurodegenerative disease or disorder (e.g., Parkinson's disease) in apatient in need thereof, comprising administering to the patient atherapeutically effecetive amount of a compound or composition providedherein.

The present disclosure also provides compounds for use in method ofinhibiting a ubiquitin-specific protease (e.g., USP30) in a patient inneed thereof. In some embodiments, the present disclosure providescompounds for use in a method of treating a neurodegenerative disease ordisorder (e.g., Parkinson's disease) in a patient in need thereof.

Synthesis of Compounds Disclosed Herein

The compounds and pharmaceutically acceptable salts disclosed herein maybe prepared by methods known in the art of organic synthesis as setforth in part by the following synthetic schemes. In the schemesdescribed below, it is well understood that protecting groups forsensitive or reactive groups are employed where necessary in accordancewith general principles of chemistry. Protecting groups are manipulatedaccording to standard methods of organic synthesis (T. W. Greene and P.G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition,Wiley, New York 1999). These groups are removed at a convenient stage ofthe compound synthesis using methods that are readily apparent to thoseskilled in the art.

In general, the compounds of formula (I) can be synthesized by themethods outlined in Scheme 1, by the specific procedures discussed inExamples 2-4, and/or by methods otherwise known to one skilled in theart. The starting materials for the synthesis described in Scheme 1 arecommercially available or can be prepared by methods known to oneskilled in the art.

Exemplary Embodiments

The following numbered embodiments, while non-limiting, are exemplary ofcertain aspects of the disclosure:

-   1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Ar¹ is phenylene or 5-6 membered heteroarylene, wherein said phenyleneor heteroarylene is substituted with m R¹ groups;

Ar² is phenylene or 5-6 membered heteroarylene, wherein said phenyleneor heteroarylene is substituted with n R² groups;

L is —O—, —S—, —NR³—, —C(R⁴)₂—, —S(O)₂—, or —S(O)—;

M is 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl,wherein said cycloalkyl, phenyl, or heteroaryl is substituted withp R⁵groups;

each occurrence of R¹, R², and R⁵ is independently halo, cyano, NO₂,oxo, hydroxyl, —R⁶, —OR⁶, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, —C₁-C₆ alkylene-R⁶, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, —C₀-C₃alkylene-NR⁶R⁷, —C₀-C₃ alkylene-NR⁷R⁸, —C₀-C₃ alkylene-C(O)NR⁶R⁷, —C₀-C₃alkylene-C(O)NR⁷R⁸, —C₀-C₃ alkylene-NR⁷C(O)R⁶, —C₀-C₃alkylene-NR⁷C(O)R⁸, —C₀-C₃ alkylene-NR⁷S(O)₂R⁶, —C₀-C₃ alkylene-C(O)R⁶,—C₀-C₃ alkylene-C(O)R⁷, —C₀-C₃ alkylene-SR⁶, —C₀-C₃ alkylene-S(O)R⁶,—C₀-C₃ alkylene-S(O)₂R⁶, —C₀-C₃ alkylene-S(O)₂R⁷, —C₀-C₃alkylene-S(O)₂NR⁶R⁷, —C₀-C₃ alkylene-S(O)₂NR⁷R⁸, —C₀-C₃alkylene-NR⁷C(O)NR⁸R⁹, —C₀-C₃ alkylene-NR⁷S(O)₂NR⁸R⁹, —C₀-C₃alkylene-C(O)OR⁷, —C₀-C₃ alkylene-C(O)OR⁶, —C₀-C₃ alkylene-OC(O)R⁷,—C₀-C₃ alkylene-OC(O)R⁶, —C₀-C₃ alkylene-NR⁷C(O)OR⁸, or —C₀-C₃alkylene-NR⁷S(O)₂R⁸;

R³ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

each R⁴ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or two R⁴groups together with the carbon atom to which they are attached form a3-6 membered cycloalkyl or heterocycloalkyl;

each R⁶ is independently 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, 6-10 membered aryl, or 3-8 membered cycloalkyl,wherein said heteroaryl, heterocycloalkyl, aryl, or cycloalkyl isoptionally substituted with 1-5 substituents independently selected fromthe group consisting of halo, oxo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10membered aryl, 3-8 membered cycloalkyl, —NR¹⁰C(O)NR¹¹R¹², —NR¹⁰R¹¹,—C(O)R¹⁰, —NR¹⁰C(O)R¹¹, —NR¹⁰C(O)OR¹¹, —S(O)₂R¹⁰, —C(O)NR¹⁰R¹¹,—C(O)OR¹⁰, —S(O)₂NR¹⁰R¹¹, —NR¹⁰S(O)₂R¹¹, —OR¹⁰, —OC(O)R¹⁰, —OS(O)₂R¹⁰,—OC(O)NR¹⁰R¹¹, —OC(O)OR¹⁰, —OS(O)₂NR¹⁰R¹¹, —C(O)R¹⁰,—C(O)NR¹⁰C(O)NR¹¹R¹², —C(O)NR¹⁰R¹¹, —C(O)C(O)R¹⁰, —C(O)NR¹⁰C(O)R¹¹,—C(O)NR¹⁰C(O)OR¹¹, —C(O)S(O)₂R¹⁰, —C(O)C(O)NR¹⁰R¹¹, —C(O)C(O)OR¹⁰,—C(O)S(O)₂NR¹⁰R¹¹, —C(O)NR¹⁰S(O)₂R¹¹, —C₁-C₆ alkylene-R¹⁰, —C₁-C₆alkylene-NR¹⁰C(O)NR¹¹R¹², —C₁-C₆ alkylene-NR¹⁰R¹¹, —C₁-C₆alkylene-C(O)R¹⁰, —C₁-C₆ alkylene-NR¹⁰C(O)R¹¹, —C₁-C₆alkylene-NR¹⁰C(O)OR¹¹, —C₁-C₆ alkylene-S(O)₂R¹⁰, —C₁-C₆alkylene-C(O)NR¹⁰R¹¹, —C₁-C₆ alkylene-C(O)OR¹⁰, —C₁-C₆alkylene-S(O)₂NR¹⁰R¹¹, —C₁-C₆ alkylene-NR¹⁰S(O)₂R¹¹, —C₁-C₆alkenylene-R¹⁰, —C₁-C₆ alkenylene-NR¹⁰C(O)NR¹¹R¹², —C₁-C₆alkenylene-NR¹⁰R¹¹, —C₁-C₆ alkenylene-C(O)R¹⁰, —C₁-C₆alkenylene-NR¹⁰C(O)R¹¹, —C₁-C₆ alkenylene-NR¹⁰C(O)OR¹¹, —C₁-C₆alkenylene-S(O)₂R¹⁰, —C₁-C₆ alkenylene-C(O)NR¹⁰R¹¹, —C₁-C₆alkenylene-C(O)OR¹⁰, —C₁-C₆ alkenylene-S(O)₂NR¹⁰R¹¹, and —C₁-C₆alkenylene-NR¹⁰S(O)₂R¹¹;

each R⁷, R⁸, and R⁹ is independently hydrogen or C₁-C₆ alkyl;

each R¹⁰, R¹¹, and R¹² is independently hydrogen, C₁-C₆ alkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl,or 3-8 membered cycloalkyl;

m is 0-4;

n is 0-4;

p is 0-4;

R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) are definedas follows:

-   -   (i) R^(a) and R^(b) form a C₁-C₄ alkylene group between the        atoms to which they are attached, wherein said C₁-C₄ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (ii) R^(a) and R^(e) form a C₁-C₂ alkylene group between the        atoms to which they are attached, wherein said C₁-C₂ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(b), R^(c), R^(d), R^(f), R^(g), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (iii) R^(a) and R^(g) form a C₁-C₃ alkylene group between the        atoms to which they are attached, wherein said C₁-C₃ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(b), R^(c), R^(d), R^(e), R^(f), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (iv) R^(b) and R^(c) form a C₁-C₄ alkylene group between the        atoms to which they are attached, wherein said C₁-C₄ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(a), R^(d), R^(e), R^(f), R^(g), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (v) R^(b) and R^(c) form a C₁-C₃ alkylene group between the        atoms to which they are attached, wherein said C₁-C₄ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(a), R^(c), R^(d), R^(f), R^(g), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (vi) R^(b) and R^(g) form a C₁-C₄ alkylene group between the        atoms to which they are attached, wherein said C₁-C₃ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(a), R^(e), R^(d), R^(e), R^(f), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (vii) R^(c) and R^(d) together with the atom to which they are        attached, form a 3-6 membered cycloalkyl or heterocycloalkyl,        wherein said 3-6 membered cycloalkyl or heterocycloalkyl is        substituted with 0-4 substituents selected from the group        consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and        R^(a), R^(b), R^(e), R^(f), R^(g), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (viii) R^(c) and R^(d) together form ═O; and R^(a), R^(b),        R^(e), R^(f), R^(g), and R^(h) are each independently hydrogen,        halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl; or    -   (ix) R^(c) and R^(e) form a C₁-C₄ alkylene group between the        atoms to which they are attached, wherein said C₁-C₄ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(a), R^(b), R^(d), R^(f), R^(g), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (x) R^(c) and R^(g) form a C₁-C₃ alkylene group between the        atoms to which they are attached, wherein said C₁-C₃ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(a), R^(b), R^(d), R^(e), R^(f) and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (xi) R^(c) and R^(f) together with the atom to which they are        attached, form a 3-6 membered cycloalkyl or heterocycloalkyl,        wherein said 3-6 membered cycloalkyl or heterocycloalkyl is        substituted with 0-4 substituents selected from the group        consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and        R^(a), R^(b), R^(c), R^(d), R^(g), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (xii) R^(e) and R^(f) together form ═O; and R^(a), R^(b), R^(c),        R^(d), R_(g), and R^(h) are each independently hydrogen,        halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl; or    -   (xiii) R^(e) and R^(g) form a C₁-C₃ alkylene group between the        atoms to which they are attached, wherein said C₁-C₃ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(a), R^(b), R^(c), R^(d), R^(f), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (xiv) R^(g) and R^(h) together with the atom to which they are        attached, form a 3-6 membered cycloalkyl or heterocycloalkyl,        wherein said 3-6 membered cycloalkyl or heterocycloalkyl is        substituted with 0-4 substituents selected from the group        consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and        R^(a), R^(b), R^(c), R^(d), R^(e), and R^(f) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (xv) R^(g) and R^(h) together form ═O; and R^(a), R^(b), R^(c),        R^(d), R^(e), and R^(f) are each independently hydrogen,        halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

-   2. The compound of embodiment 1, or a pharmaceutically acceptable    salt thereof, wherein R^(c) and R^(g) form a C₁-C₃ alkylene group    between the atoms to which they are attached, wherein said C₁-C₃    alkylene group is substituted with 0-4 substituents selected from    the group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;    and R^(a), R^(b), R^(d), R^(e), R^(f), and R^(h) are each    independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

-   3. The compound of embodiment 1, or a pharmaceutically acceptable    salt thereof, wherein R^(b) and R^(c) form a C₁-C₄ alkylene group    between the atoms to which they are attached, wherein said C₁-C₄    alkylene group is substituted with 0-4 substituents selected from    the group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;    and R^(a), R^(d), R^(e), R^(f), R^(g), and R^(h) are each    independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

-   4. The compound of embodiment 1, or a pharmaceutically acceptable    salt thereof, wherein R^(c) and R^(d) together with the atom to    which they are attached, form a 3-6 membered cycloalkyl or    heterocycloalkyl, wherein said 3-6 membered cycloalkyl or    heterocycloalkyl is substituted with 0-4 substituents selected from    the group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;    and R^(a), R^(b), R^(e), R^(f), R^(g), and R^(h) are each    independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

-   5. The compound of embodiment 1, wherein the compound has formula    (I-A):

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is C or N;

X² is CH, CR¹, O, S, N, NH, or NR¹;

X³ is CH, CR¹, O, S, N, NH, or NR¹;

X⁴ is C or N;

X⁵ is a bond, CH, CR¹, O, S, N, NH, or NR¹;

X⁶ is CH, CR¹, O, S, N, NH, or NR¹;

Y¹ is C or N;

Y² is C or N;

Y³ is CH, CR², O, S, N, NH, or NR²;

Y⁴ is a bond, CH, CR², O, S, N, NH, or NR²;

Y⁵ is CH, CR², O, S, N, NH, or NW;

Y⁶ is CH, CR², O, S, N, NH, or NR²;

R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) are definedas follows:

-   -   (ii) R^(a) and R^(e) form a C₁-C₂ alkylene group between the        atoms to which they are attached, wherein said C₁-C₂ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(b), R^(c), R^(d), R^(f), R^(g), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (iv) R^(b) and R^(c) form a C₁-C₄ alkylene group between the        atoms to which they are attached, wherein said C₁-C₄ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(a), R^(d), R^(e), R^(f), R^(g), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (vii) R^(c) and R^(d) together with the atom to which they are        attached, form a 3-6 membered cycloalkyl or heterocycloalkyl,        wherein said 3-6 membered cycloalkyl or heterocycloalkyl is        substituted with 0-4 substituents selected from the group        consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and        R^(a), R^(b), R^(e), R^(f), R^(g), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (viii) R^(c) and R^(d) together form ═O; and R^(a), R^(b),        R^(e), R^(f), R^(g), and R^(h) are each independently hydrogen,        halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl; or    -   (ix) R^(c) and R^(e) form a C₁-C₄ alkylene group between the        atoms to which they are attached, wherein said C₁-C₄ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(a), R^(b), R^(d), R^(f), R^(g), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (x) R^(c) and R^(g) form a C₁-C₃ alkylene group between the        atoms to which they are attached, wherein said C₁-C₃ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(a), R^(b), R^(d), R^(e), R^(f), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (xi) R^(e) and R^(f) together with the atom to which they are        attached, form a 3-6 membered cycloalkyl or heterocycloalkyl,        wherein said 3-6 membered cycloalkyl or heterocycloalkyl is        substituted with 0-4 substituents selected from the group        consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and        R^(a), R^(b), R^(c), R^(d), R^(g), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (xiii) R^(e) and R^(g) form a C₁-C₃ alkylene group between the        atoms to which they are attached, wherein said C₁-C₃ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(a), R^(b), R^(c), R^(d), R^(f), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (xv) R^(g) and R^(h) together form ═O; and R^(a), R^(b), R^(c),        R^(d), R^(e), and R^(f) are each independently hydrogen,        halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

-   6. The compound of embodiment 5, or a pharmaceutically acceptable    salt thereof, wherein R^(c) and R^(g) form a C₁-C₃ alkylene group    between the atoms to which they are attached, wherein said C₁-C₃    alkylene group is substituted with 0-4 substituents selected from    the group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;    and R^(a), R^(b), R^(d), R^(e), R^(f), and R^(h) are each    independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

-   7. The compound of embodiment 5, or a pharmaceutically acceptable    salt thereof, wherein R^(b) and R^(c) form a C₁-C₄ alkylene group    between the atoms to which they are attached, wherein said C₁-C₄    alkylene group is substituted with 0-4 substituents selected from    the group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;    and R^(a), R^(d), R^(e), R^(f), R^(g), and R^(h) are each    independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

-   8. The compound of embodiment 5, or a pharmaceutically acceptable    salt thereof, wherein R^(c) and R^(d) together with the atom to    which they are attached, form a 3-6 membered cycloalkyl or    heterocycloalkyl, wherein said 3-6 membered cycloalkyl or    heterocycloalkyl is substituted with 0-4 substituents selected from    the group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;    and R^(a), R^(b), R^(e), R^(f), R^(g), and R^(h) are each    independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

-   9. The compound of any one of embodiments 5-8, or a pharmaceutically    acceptable salt thereof, wherein X¹ is C; X² is N; X³ is NH; X⁴ is    C; X⁵ is a bond; and X⁶ is CH.

-   10. The compound of any one of embodiments 5-9, or a    pharmaceutically acceptable salt thereof, wherein Y¹ is C; Y² is C;    Y³ is CH; Y⁴ is CH; Y⁵ is CH; and Y⁶ is CH.

-   11. The compound of any one of embodiments 5-10, or a    pharmaceutically acceptable salt thereof, wherein L is O.

-   12. The compound of any one of embodiments 5-11, or a    pharmaceutically acceptable salt thereof, wherein M is phenyl    substituted withp R⁵ groups.

-   13. The compound of embodiment 1, wherein the compound has formula    (I-B):

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is C or N;

X² is CH, CR¹, O, S, N, NH, or NR¹;

X³ is CH, CR¹, O, S, N, NH, or NR¹;

X⁴ is C or N;

X⁶ is CH, CR¹, O, S, N, NH, or NR¹;

Y³ is CH, CR², or N,

Y⁴ is CH, CR², or N;

Y⁵ is CH, CR², or N;

Y⁶ is CH, CR², or N;

R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) are definedas follows:

-   -   (ii) R^(a) and R^(e) form a C₁-C₂ alkylene group between the        atoms to which they are attached, wherein said C₁-C₂ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(b), R^(c), R^(d), R^(f), R^(g), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (iv) R^(b) and R^(c) form a C₁-C₄ alkylene group between the        atoms to which they are attached, wherein said C₁-C₄ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(a), R^(d), R^(e), R^(f), R^(g), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (vii) R^(c) and R^(d) together with the atom to which they are        attached, form a 3-6 membered cycloalkyl or heterocycloalkyl,        wherein said 3-6 membered cycloalkyl or heterocycloalkyl is        substituted with 0-4 substituents selected from the group        consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and        R^(a), R^(b), R^(e), R^(f), R^(g), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (viii) R^(c) and R^(d) together form ═O; and R^(a), R^(b),        R^(e), R^(g), and R^(h) are each independently hydrogen,        halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl; or    -   (ix) R^(c) and R^(e) form a C₁-C₄ alkylene group between the        atoms to which they are attached, wherein said C₁-C₄ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(a), R^(b), R^(d), R^(f), R^(g), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (x) R^(c) and R^(g) form a C₁-C₃ alkylene group between the        atoms to which they are attached, wherein said C₁-C₃ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(a), R^(b), R^(d), R^(e), R^(f), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (xi) R^(e) and R^(f) together with the atom to which they are        attached, form a 3-6 membered cycloalkyl or heterocycloalkyl,        wherein said 3-6 membered cycloalkyl or heterocycloalkyl is        substituted with 0-4 substituents selected from the group        consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and        R^(a), R^(b), R^(c), R^(d), R^(g), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (xiii) R^(e) and R^(g) form a C₁-C₃ alkylene group between the        atoms to which they are attached, wherein said C₁-C₃ alkylene        group is substituted with 0-4 substituents selected from the        group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;        and R^(a), R^(b), R^(e), R^(d), R^(f), and R^(h) are each        independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃        haloalkyl; or    -   (xv) R^(g) and R^(h) together form ═O; and R^(a), R^(b), R^(C),        R^(d), R^(e), and R^(f) are each independently hydrogen,        halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

-   14. The compound of embodiment 13, or a pharmaceutically acceptable    salt thereof, wherein R^(c) and R^(g) form a C₁-C₃ alkylene group    between the atoms to which they are attached, wherein said C₁-C₃    alkylene group is substituted with 0-4 substituents selected from    the group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;    and R^(a), R^(b), R^(d), R^(e), R^(f), and R^(h) are each    independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

-   15. The compound of embodiment 13, or a pharmaceutically acceptable    salt thereof, wherein R^(b) and R^(c) form a C₁-C₄ alkylene group    between the atoms to which they are attached, wherein said C₁-C₄    alkylene group is substituted with 0-4 substituents selected from    the group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;    and R^(a), R^(d), R^(e), R^(f), R^(g), and R^(h) are each    independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

-   16. The compound of embodiment 13, or a pharmaceutically acceptable    salt thereof, wherein R^(c) and R^(d) together with the atom to    which they are attached, form a 3-6 membered cycloalkyl or    heterocycloalkyl, wherein said 3-6 membered cycloalkyl or    heterocycloalkyl is substituted with 0-4 substituents selected from    the group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;    and R^(a), R^(b), R^(e), R^(f), R^(g), and R^(h) are each    independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

-   17. The compound of any one of embodiments 13-16, or a    pharmaceutically acceptable salt thereof, wherein X¹ is C; X² is N;    X³ is NH; X⁴ is C; and X⁶ is CH.

-   18. The compound of any one of embodiments 13-17, or a    pharmaceutically acceptable salt thereof, wherein Y¹ is C; Y² is C;    Y³ is CH; Y⁴ is CH; Y⁵ is CH; and Y⁶ is CH.

-   19. The compound of any one of embodiments 13-18, or a    pharmaceutically acceptable salt thereof, wherein L is O.

-   20. The compound of any one of embodiments 13-19, or a    pharmaceutically acceptable salt thereof, wherein M is phenyl    substituted with p R⁵ groups.

-   21. The compound of embodiment 1, wherein the compound has formula    (I-C):

or a pharmaceutically acceptable salt thereof, wherein:

R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), and R^(h) are definedas follows:

-   -   (ii) R^(a) and R^(e) form a C₁-C₂ alkylene group between the        atoms to which they are attached; and R^(b), R^(c), R^(d),        R^(f), R^(g), and R^(h) are each hydrogen; or    -   (iv) R^(b) and R^(c) form a C₁-C₄ alkylene group between the        atoms to which they are attached; and R^(a), R^(d), R^(e),        R^(f), R^(g), and R^(h) are each hydrogen; or    -   (vii) R^(c) and R^(d) together with the atom to which they are        attached, form a 3-6 membered cycloalkyl or heterocycloalkyl;        and R^(a), R^(b), R^(e), R^(f), R^(g), and R^(h) are each        hydrogen; or    -   (viii) R^(c) and R^(d) together form ═O; and R^(a), R^(b),        R^(e), R^(f), R^(g) and R^(h) are each hydrogen; or    -   (ix) R^(c) and R^(e) form a C₁-C₄ alkylene group between the        atoms to which they are attached; and R^(a), R^(b), R^(d),        R^(f), R^(g), and R^(h) are each hydrogen; or    -   (x) R^(c) and R^(g) form a C₁-C₃ alkylene group between the        atoms to which they are attached; and R^(a), R^(b), R^(d),        R^(e), R^(f), and R^(h) are each hydrogen; or    -   (xi) R^(e) and R^(f) together with the atom to which they are        attached, form a 3-6 membered cycloalkyl or heterocycloalkyl;        and R^(a), R^(b), R^(c), R^(d), R^(g), and R^(h) are each        hydrogen; or    -   (xiii) R^(e) and R^(g) form a C₁-C₃ alkylene group between the        atoms to which they are attached; and R^(a), R^(b), R^(c),        R^(d), R^(f), and R^(h) are each independently hydrogen or    -   (xv) R^(g) and R^(h) together form ═O; and R^(a), R^(b), R^(c),        R^(d), R^(e), and R^(f) are each hydrogen.

-   22. The compound of embodiment 21, or a pharmaceutically acceptable    salt thereof, wherein R^(a), R^(b), R^(e), R^(d), R^(e), R^(f),    R^(g), and R^(h) are defined as follows:    -   (ii) R^(a) and R^(e) form a C₁-C2 alk_(y)lene group between the        atoms to which they are attached; and R^(b), R^(c), R^(d),        R^(f), R^(g), and R^(h) are each hydrogen; or    -   (iv) R^(b) and Re form a C₁-C₃ alkylene group between the atoms        to which they are attached; and R^(a), R^(d), R^(e), R^(f),        R^(g), and R^(h) are each hydrogen; or    -   (vii) R^(c) and R^(d) together with the atom to which they are        attached, form a 3-membered cycloalkyl or a 4-membered        heterocycloalkyl; and R^(a), R^(b), R^(e), R^(f), R^(g), and        R^(h) are each hydrogen; or    -   (viii) R^(c) and R^(d) together form ═O; and R^(a), R^(b),        R^(e), R^(f), R^(g), and R^(h) are each hydrogen; or    -   (ix) R^(c) and R^(e) form a C₂ alkylene group between the atoms        to which they are attached; and R^(a), R^(b), R^(d), R^(f),        R^(g), and R^(h) are each hydrogen; or    -   (x) R^(c) and R^(g) form a C₁-C₂ alkylene group between the        atoms to which they are attached; and R^(a), R^(b), R^(d),        R^(e), R^(f), and R^(h) are each hydrogen; or    -   (xi) R^(e) and R^(f) together with the atom to which they are        attached, form a 4-membered heterocycloalkyl; and R^(a), R^(b),        R^(c), R^(d), R^(g), and R^(h) are each hydrogen; or    -   (xiii) R^(e) and R^(g) form a C₂ alkylene group between the        atoms to which they are attached; and R^(a), R^(b), R^(c),        R^(d), R^(f), and R^(h) are each independently hydrogen or    -   (xv) R^(g) and R^(h) together form ═O; and R^(a), R^(b), R^(c),        R^(d), R^(e), and R^(f) are each hydrogen.

-   23. The compound of embodiment 22, or a pharmaceutically acceptable    salt thereof, wherein R^(c) and R^(g) form a C₁-C₂ alkylene group    between the atoms to which they are attached; and R^(a), R^(b),    R^(d), R^(e), R^(f), and R^(h) are each hydrogen.

-   24. The compound of embodiment 22, or a pharmaceutically acceptable    salt thereof, wherein R^(b) and R^(c) form a C₁-C₃ alkylene group    between the atoms to which they are attached; and R^(a), R^(d),    R^(e), R^(f), R^(g), and R^(h) are each hydrogen.

-   25. The compound of embodiment 22, or a pharmaceutically acceptable    salt thereof, wherein R^(e) and R^(d) together with the atom to    which they are attached, form a 3-membered cycloalkyl or a    4-membered heterocycloalkyl; and R^(a), R^(b), R^(e), R^(f), R^(g),    and R^(h) are each hydrogen.

-   26. The compound of any one of embodiments 21-25, or a    pharmaceutically acceptable salt thereof, wherein n and p are 0.

-   27. The compound of embodiment 1, or a pharmaceutically acceptable    salt thereof, wherein the compound is selected from Table 1.

-   28. The compound of embodiment 1, or a pharmaceutically acceptable    salt thereof, wherein the compound is selected from Table 2.

-   29. The compound of any one of embodiments 1-28, or a    pharmaceutically acceptable salt thereof, that is a USP30 Inhibitor    Compound having an IC50 value of ≤1 μM as measured in a    Ubiquitin-Rhodamine 110 Assay as described in Example 1.

-   30. The compound of embodiment 29, or a pharmaceutically acceptable    salt thereof, wherein the IC50 value is ≤0.1 μM.

-   31. A compound of formula (I-C)

or a pharmaceutically acceptable salt thereof, that is a USP30 InhibitorCompound having an IC₅₀ value of ≤1 μM and >0.001 μM as measured in aUbiquitin-Rhodamine 110 Assay as described in Example 1, wherein:

each occurrence of R² and R⁵ is independently halo, cyano, hydroxyl,C₁-C₆ alkyl, C₁-C₆ alkoxyl, C₁-C₆ haloalkyl, and C₁-C₆ hydroxyalkyl;

n is 0-4;

p is 0-4;

R^(h) is hydrogen;

R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), and R^(g) are defined asfollows:

-   -   (ii) R^(a) and R^(e) form a C₁-C₂ alkylene group between the        atoms to which they are attached; and R^(b), R^(c), R^(d),        R^(f), and R^(g) are each hydrogen; or    -   (iv) R^(b) and R^(c) form a C₁-C₂ alkylene group between the        atoms to which they are attached; and R^(a), R^(e), R^(d),        R^(f), and R^(g) are each hydrogen; or    -   (vii) R^(c) and R^(d) together with the atom to which they are        attached, form a 3 membered cycloalkyl; and R^(a), R^(b), R^(e),        R^(f), and R_(g) are each hydrogen; or    -   (x) R^(c) and R^(g) form a C₁-C₂ alkylene group between the        atoms to which they are attached; and R^(a), R^(b), R^(d),        R^(e), and R^(f) are each hydrogen; or    -   (xi) R^(e) and R^(f) together with the atom to which they are        attached, form a 4 membered heterocycloalkyl; and R^(a), R^(b),        R^(c), R^(d), and R^(g) are each hydrogen; or    -   (xiii) R^(c) and R^(g) form a C₂ alkylene group between the        atoms to which they are attached; and R^(a), R^(b), R^(c),        R^(d), and R^(f) are each independently hydrogen.

-   32. The compound of embodiment 31, or a pharmaceutically acceptable    salt thereof, wherein the compound has the following formula

-   33. The compound of embodiment 31, or a pharmaceutically acceptable    salt thereof, wherein the compound has the following formula

-   34. The compound of embodiment 31, or a pharmaceutically acceptable    salt thereof, wherein the compound has the following formula

-   35. The compound of embodiment 31, or a pharmaceutically acceptable    salt thereof, wherein the compound has the following formula

-   36. The compound of any one of embodiments 31-35, or a    pharmaceutically acceptable salt thereof, wherein n and p are 0.-   37. A pharmaceutical composition comprising the compound of any one    of embodiments 1-36, or a pharmaceutically acceptable salt thereof,    and a pharmaceutically acceptable carrier.-   38. A method of inhibiting a ubiquitin-specific protease in a    patient in need thereof, comprising administering to the patient a    therapeutically effective amount of the compound of any one of    embodiments 1-36, or a pharmaceutically acceptable salt thereof, or    the pharmaceutical composition of embodiment 37.-   39. The method of embodiment 38, wherein the ubiquitin-specific    protease is USP30.-   40. A method of treating a neurodegenerative disorder in a patient    in need thereof, comprising administering to the patient a    therapeutically effective amount of the compound of any one of    embodiments 1-36, or a pharmaceutically acceptable salt thereof, or    the pharmaceutical composition of embodiment 37.-   41. The method of embodiment 40, wherein the neurodegenerative    disorder is Parkinson's Disease.-   42. A compound of any one of embodiments 1-36, or a pharmaceutically    acceptable salt thereof, for use in a method of inhibiting a    ubiquitin-specific protease in a patient in need thereof.-   43. The compound or pharmaceutically acceptable salt for use of    embodiment 42, wherein the ubiquitin-specific protease is USP30.

044. A compound of any one of embodiments 1-36, or a pharmaceuticallyacceptable salt thereof, for use in a method of treating aneurodegenerative disorder in a patient in need thereof.

-   45. The compound or pharmaceutically acceptable salt for use of    embodiment 44, wherein the neurodegenerative disorder is Parkinson's    Disease.-   46. A USP30 Inhibitor Compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

each occurrence of R² and R⁵ is independently halo, cyano, hydroxyl,C₁-C₆ alkyl, C₁-C₆ alkoxyl, C₁-C₆ haloalkyl, or C₁-C₆ hydroxyalkyl;

n is 0-4;

p is 0-4.

-   47. The compound of any one of embodiments 1-36 or 44-46, having an    IC₅₀ value of ≤0.5 μM and >0.001 μM as measured in a    Ubiquitin-Rhodamine 110 Assay as described in Example 1.-   48. The compound of embodiment 47, having an IC₅₀ value of ≤0.1 μM    and >0.001 μM as measured in a Ubiquitin-Rhodamine 110 Assay as    described in Example 1.-   49. A USP30 Inhibitor Compound as disclosed and provided herein.-   50. The USP30 Inhibitor Compound of embodiment 49, having an IC₅₀    value of ≤1 μM and >0.001 μM as measured in a Ubiquitin-Rhodamine    110 Assay as described in Example 1.

EXAMPLES General Methods

All solvents used were commercially available and were used withoutfurther purification. Reactions were typically run using anhydroussolvents under an inert atmosphere of nitrogen.

Proton NMR spectra were recorded using a Broker Plus 400 NMRSpectrometer. The deuterated solvent (DMSO-d₆) typically contained 0.03%to 0.05% v/v tetramethylsilane, which was used as the reference signal(set at δ 0.00 for 1H).

LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC20-AD and LCMS 2020 MS detector. The column used was a Shim-pack XR-ODS,2.2 μm, 3.0×50 mm. The instrument uses reverse-phase conditions(acetonitrile/water, containing 0.05% ammonia).

Abbreviations

Unless otherwise noted, or where the context dictates otherwise, thefollowing abbreviations shall be understood to have the followingmeanings:

-   δ chemical shift-   ACN Acetonitrile-   DIEA N,N-Diisopropylethylamine-   DMF N,N-Dimethylformamide-   DCM Dichloromethane or methylene chloride-   h hour-   ¹H NMR proton nuclear magnetic resonance-   HATU    2-(3H-[1,2,3]Triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium    hexafluorophosphate-   HPLC high performance liquid chromatography-   Hz Hertz-   LCMS liquid chromatography/mass spectrometry-   min minutes-   MS mass spectrometry-   ppm parts per million-   RT retention time-   SEMCl 2-chloromethyl 2-(trimethylsilyl)ethyl ether-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   XPhos-Pd    Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)    (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)    methanesulfonate-   XPhos-Pd-G3

Example 1 Ubiquitin-Rhodamine 110 Assay for USP30 Activity

The assay was performed in a final volume of 9 μL in assay buffercontaining 20 mM Tris-HCl (pH 8.0, (1M Tris-HCl, pH 8.0 solution;Corning 46-031-CM)), 1 mM GSH (L-glutathione reduced, Sigma-Aldrich,G4251-100G), 0.03% BGG (0.22 μM filtered, Sigma, G7516-25G), and 0.01%Triton X-100 (Sigma, T9284-10L). Nanoliter quantities of 10-point,3-fold serial dilution in DMSO were pre-dispensed into 1536 assay plates(Corning, #3724BC) for a final test concentration of 25 μM to 1.3 nM,top to lowest dose, respectively. Concentration and incubation timeswere optimized for the maximal signal-to-background while maintaininginitial velocity conditions at a fixed substrate concentration. Thefinal concentration of USP30 (human recombinant USP30, Boston Biochem,cat. #E-582) in the assay was 0.2 nM. Final substrate (Ub-Rh110;Ubiquitin-Rhodamine 110, UbiQ-126) concentration was 25 nM with[Ub-Rh110]<<Km. 3 μL of 2×USP30 was added to assay plates (pre-stampedwith compound), preincubated for 30 minutes and then treated with 3 μLof 2×Ub-Rh110. Plates were incubated for 30 minutes at room temperaturebefore addition of 3 μL of stop solution (final concentration of 10 mMcitric acid (Sigma, 251275-500G)). Fluorescence was read on the Envision(excitation at 485 nm and emission at 535 nm; Perkin Elmer) or on thePheraSTAR (excitation at 485 nm and emission at 535 nm; BMG Labtech)fluorescence reader.

For all assay formats, data were reported as percent inhibition comparedwith control wells based on the following equation: %inh=1−((FLU−AveLow)/(AveHigh−AveLow)) where FLU=measured Fluorescence,AveLow=average Fluorescence of no enzyme control (n=16), andAveHigh=average Fluorescence of DMSO control (n=16). IC₅₀ values weredetermined by curve fitting of the standard 4 parameter logistic fittingalgorithm included in the Activity Base software package: IDBS XEDesigner Mode1205. Data is fitted using the Levenburg Marquardtalgorithm.

The calculated IC₅₀ values of the compounds described herein arereported in Table 3, where A represents an IC₅₀ of <0.1 μM, B representsan IC₅₀ of 0.1 to 1.0 μM, and C represents an IC₅₀ of >1.0 μM. Compoundsin the USP30 biochemical assay were deemed active if the IC₅₀ was ≤1 μM.

TABLE 3 IC₅₀ Values of Compounds in Ubiquitin-Rhodamine 110 AssayCompound IC₅₀ (μM)  1-a B  1b A  2-a A  2-b C  3-a B  3-b A  4-a B  4-bB  5-a A  5-b B  6-a A  6-b B  7-a A  7-b B  8-a B  8-b B  9-a C  9-b C13-a A 13-b A 20-a A 20-b A

Example 2 Preparation of(1S,5R)-2-(5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl)-2,6-diazabicyclo[3.2.1]octane-6-carbonitrile(1-a) and (1R,5S)-2-(5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl)-2,6-diazabicyclo[3.2.1]octane-6-carbonitrile(1-b)

Compounds 1-a and 1-b were prepared by the following route:

Step 1. Methyl5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate

2-Chloromethyl 2-(trimethylsilyl)ethyl ether (12.3 mL, 69.5 mmol) wasadded to a mixture of methyl 5-bromo-1H-pyrazole-3-carboxylate (5.00 g,23.2 mmol) and K₂CO₃ (18.0 g, 130 mmol) in DMF (50 mL) at 0° C. in anice/water bath. The resulting solution was stirred for 14 h at 25° C.The reaction was quenched by the addition of water (100 mL). Theresulting mixture was extracted with ethyl acetate (3×100 mL). Thecombined organic layers were washed with brine (100 mL), dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was purified by silica gel chromatography (eluting with 15:1petroleum ether/ethyl acetate) to afford methyl5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylateas a yellow oil (6.20 g, 79%). LCMS (ES, m/z) 335, 337 [M+H]⁺.

Step 2. Methyl5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate

A solution of methyl5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate(6.20 g, 18.4 mmol), (2-phenoxyphenyl)boronic acid (4.96 g, 23.2 mmol),XPhos-Pd (2.90 g, 3.68 mmol) and K₃PO₄ (11.7 g, 55.2 mmol) in dioxane(120 mL) and H₂O (24 mL) was stirred for 15 h at 100° C. in an oil bath.After cooling to 25° C., the solids were filtered out. The filtrate wasconcentrated under vacuum. The residue was diluted with water (50 mL).The resulting mixture was extracted with ethyl acetate (3×50 mL). Thecombined organic layer was dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was purified byreverse phase chromatography (Column:)(Bridge Shield RP18 OBD Column, 5μm, 30×150 mm; Mobile phase, A: water (containing 10 mmol/L NH₄HCO₃) andB: ACN (5% B to 72% over 20 min); Detector: UV:220 and 254 nm) to affordmethyl5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylateas a yellow solid (3.20 g, 41%). LCMS (ES, m/z) 425 [M+H]⁺.

Step 3.5-(2-Phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylicacid

A solution of methyl5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate(1.40 g, 3.30 mmol) and LiOH (0.810 g, 33.8 mmol) in THF (60 mL) and H₂O(15 mL) was stirred for 4 h at 50° C. The mixture was allowed to cool to25° C. and concentrated under vacuum. The pH value of the residue wasadjusted to 5-6 with 3 N hydrochloric acid. The solids were collected byfiltration and dried in an oven to afford5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylic acid as an off-white solid (1.05 g,78%). LCMS (ES, m/z) 411 [M+H]⁺.

Step 4. tert-butyl2-[5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane-6-carboxylate

A solution of5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylicacid (150 mg, 0.366 mmol), HATU (210 mg, 0.541 mmol), tert-butyl2,6-diazabicyclo[3.2.1]octane-6-carboxylate (75.0 mg, 0.346 mmol) andDIEA (0.2 mL, 1.40 mmol) in DMF (2 mL) was stirred for 3 h at 25° C. Thereaction was quenched by the addition of water (10 mL). The resultingmixture was extracted with ethyl acetate (3×20 mL). The combined organiclayer was washed with brine (20 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluting with 1/1petroleum ether/ethyl acetate) to afford tert-butyl2-[5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane-6-carboxylateas a white solid (100 mg, 45%). LCMS (ES, m/z): 605 [M+H]⁺.

Step 5.2-[5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane2,2,2-trifluoroacetate

A solution of tert-butyl2-[5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane-6-carboxylate(100 mg, 0.157 mmol) and TFA (1 mL) in DCM (2 mL) was stirred for 2 h at25° C. The resulting mixture was concentrated under vacuum to afford2-[5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane2,2,2-trifluoroacetate as a colorless oil (110 mg, crude). LCMS (ES,m/z): 375 [M+H]⁺.

Step 6.2-[5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane-6-carbonitrile

Cyanogen bromide (17.8 mg, 0.170 mmol) was added to a 0° C. mixture of2-[5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane2,2,2-trifluoroacetate (80.0 mg, 0.170 mmol) and NaHCO₃ (82.0 mg, 0.957mmol) in DMF (2 mL). The resulting mixture stirred for 16 h at 25° C.The reaction was quenched by the addition of water (10 mL). Theresulting mixture was extracted with ethyl acetate (3×20 mL). Thecombined organic layer was dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5μm,19×150 mm; Mobile Phase A: water (containing 10 mmol/L NH₄HCO₃) andB: CH₃CN (30% to 55% in 8 min); Flow rate: 25 mL/min; Detector: 220 nm)to afford2-[5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane-6-carbonitrileas a white solid (40.0 mg, 59%). LCMS (ES, m/z): 400 [M+H]⁺.

Step 7.(1S,5R)-2-(5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl)-2,6-diazabicyclo[3.2.1]octane-6-carbonitrileand(1R,5S)-2-(5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl)-2,6-diazabicyclo[3.2.1]octane-6-carbonitrile

2-[5-(2-Phenoxyphenyl)-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane-6-carbonitrile(40.0 mg, 0.100 mmol) was separated by chiral-HPLC (Column: CHIRAL ARTCellulose-SB, 2×25 cm, Sum; Mobile Phase A: n-hexane and B: EtOH (hold50% in 15 min); Flow rate: 20 mL/min; Detector: 254/220 nm; RT₁: 8.911min and RT₂: 11.119 min). The first eluting isomer (RT₁=8.911 min) wascollected and concentrated under vacuum, then lyophilized to obtain acompound for which the absolute stereochemistry was arbitrarily assignedas(1S,5R)-2-(5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl)-2,6-diazabicyclo[3.2.1]octane-6-carbonitrile(1-a) as a white solid (13.8 mg, 35%). LCMS (ES, m/z): 400 [M+H]⁺;¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 13.63 (br s, 1H), 7.86-7.85 (m, 1H),7.44-7.29 (m, 4H), 7.13-6.90 (m, 5H), 5.49-5.18 (m, 1H), 4.65-4.31 (m,1H), 4.18-4.17 (m, 1H), 3.65-3.46 (m, 3H), 3.08-3.03 (m, 1H), 1.86-1.72(m, 4H). The second eluting isomer (RT₂=11.119 min) was collected andconcentrated under vacuum, then lyophilized to obtain a compound forwhich the absolute stereochemistry was arbitrarily assigned as(1R,5S)-2-(5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl)-2,6-diazabicyclo[3.2.1]octane-6-carbonitrile(1-b) as a white solid (14.8 mg, 37%). LCMS (ES, m/z): 400 [M+H]⁺;¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 13.63 (br s, 1H), 7.88-7.85 (m, 1H),7.44-7.29 (m, 4H), 7.14-6.90 (m, 5H), 5.48-5.17 (m, 1H), 4.65-4.31 (m,1H), 4.18-4.17 (m, 1H), 3.65-3.48 (m, 3H), 3.08-3.03 (m, 1H), 1.86-1. 72(m, 4H).

The compounds set forth in Table 4 were prepared by methods analogous tothe preparation of compounds 1-a and 1-b. Each pair of compounds listedin Table 4 (i.e., compounds 2-a and 2-b, compounds 3-a and 3-b, etc.)was obtained as a racemic mixture, and were then separated by chiralHPLC according to the procedure described in Example 2, Step 7, toobtain the individual compounds in substantially enantiomerically pureform. The first and second eluting enantiomer of each enantiomer pair isidentified in Table 4. The absolute stereochemistry of each enantiomerwas arbitrarily assigned.

TABLE 4 Additional Compounds Prepared By Analogous Methods MS (ESI, Cmpdm/z) ¹H-NMR No. Structure IUPAC name [M + H]⁺ δ (ppm) 2-a

N- ((1S,4S,7S)-2- cyano-2- azabicyclo[2.2.1] heptan-7- yl)-5-(2-phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 400 ¹HNMR (DMSO-d_(6,) 400MHz) δ (ppm): 13.7-13.6 (m, 1H), 8.42-8.15 (m, 1H), 8.04-7.85(m, 1H),7.42-7.29 (m, 4H), 7.15-7.10 (m, 1H), 7.02-6.95 (m, 4H), 4.06-4.04 (m,1H), 3.84-3.82 (m, 1H), 3.52-3.49 (m, 1H), 3.10-3.06 (m, 1H), 2.67-2.62(m, 1H), 1.97-1.88 (m, 1H), 1.84-1.71 (m, 2H), 1.54-1.48 (m, 1H). 2-b

N- ((1R,4R,7R)- 2-cyano-2- azabicyclo[2.2.1] heptan-7- yl)-5-(2-phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 400 ¹HNMR (DMSO-d_(6,) 400MHz) δ (ppm): 13.8-13.6 (m, 1H), 8.57-8.15 (m, 1H), 8.02-7.86 (m, 1H),7.40-7.22 (m, 4H), 7.15-7.11 (m, 1H), 7.01-6.97 (m, 4H), 4.06-4.04 (m,1H), 3.83-3.81 (m, 1H), 3.53-3.50 (m, 1H), 3.09-3.06 (m, 1H), 2.71-2.60(m, 1H), 1.97-1.88 (m, 1H), 1.84-1.71 (m, 2H), 1.54-1.48 (m, 1H). 4-a

(1S,4S)-5-(5- (2- phenoxyphe- nyl)-1H- pyrazole-3- carbonyl)-2,5-diazabicyclo [2.2.1]heptane- 2-carbonitrile 386 ¹HNMR (DMSO-d_(6,) 400MHz) δ (ppm): 13.7 (br s, 1H), 7.91-7.89 (m, 1H), 7.44-7.37(m, 3H),7.32-7.29 (m, 1H), 7.15-7.12 (m, 1H), 7.03-6.99 (m, 4H), 5.50-5.40 (m,0.5H), 4.87-4.86 (m, 0.5H), 4.46-4.43 (m, 1H), 4.06-3.88 (m, 1H),3.65-3.51 (m, 2H), 3.36-3.34 (m, 1H), 1.99-1.85 (m, 2H). 4-b

(1R,4R)-5-(5- (2- phenoxyphe- nyl)-1H- pyrazole-3- carbonyl)-2,5-diazabicyclo [2.2.1]heptane- 2-carbonitrile 386 ¹HNMR (DMSO-d_(6,) 400MHz) δ (ppm): 13.7 (br s, 1H), 7.91-7.89 (m, 1H), 7.44-7.37(m, 3H),7.32-7.29 (m, 1H), 7.15-7.12 (m, 1H), 7.03-6.99 (m, 4H), 5.50-5.40 (m,0.5H), 4.87-4.86 (m, 0.5H), 4.46-4.43 (m, 1H), 3.99-3.88 (m, 1H),3.65-3.51 (m, 2H), 3.44-3.34 (m, 1H), 1.99-1.81 (m, 2H). 5-a

(S)-N-(5- cyano-5- azaspiro[2.4] heptan-7-yl)-5- (2- phenoxyphe-nyl)-1H- pyrazole-3- carboxamide 400 ¹HNMR (DMSO-d_(6,) 400 MHz) δ(ppm): 13.6 (br s, 1H), 8.41-8.38 (m, 1H), 7.92-7.85(m, 1H), 7.41-7.29(m, 4H), 7.15-7.12 (m, 1H), 7.02-6.91 (m, 4H), 4.25-4.20 (m, 1H),3.82-3.78 (m, 1H), 3.68-3.65 (m, 1H), 3.52-3.44 (m, 1H), 3.25-3.24 (m,1H), 0.80-0.59 (m, 4H). 5-b

(R)-N-(5- cyano-5- azaspiro[2.4] heptan-7-yl)-5- (2- phenoxyphe-nyl)-1H- pyrazole-3- carboxamide 400 ¹HNMR (DMSO-d_(6,) 400 MHz) δ(ppm): 13.6 (br s, 1H), 8.41-8.38 (m, 1H), 7.92-7.85(m, 1H), 7.41-7.29(m, 4H), 7.15-7.12 (m, 1H), 7.02-6.91 (m, 4H), 4.25-4.20 (m, 1H),3.82-3.78 (m, 1H), 3.68-3.65 (m, 1H), 3.48-3.40 (m, 1H), 3.26-3.24 (m,1H), 0.80-0.59 (m, 4H). 7-a

N- ((1S,2S,4R)- 7-cyano-7- azabicyclo[2.2.1] heptan-2- yl)-5-(2-phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 400 ¹HNMR (DMSO-d_(6,) 400MHz) δ (ppm): 13.7-13.6 (m, 1H), 8.62-8.51 (m, 1H), 8.05-7.87 (m, 1H)7.45-7.25 (m, 4H), 7.19-7.12 (m, 1H), 7.04-6.95 (m, 4H), 4.27-4.13 (m,3H), 2.22-2.08 (m, 1H), 1.83-1.65 (m, 4H). 7-b

N- ((1R,2R,4S)- 7-cyano-7- azabicyclo[2.2.1] heptan-2- yl)-5-(2-phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 400 ¹HNMR (DMSO-d_(6,) 400MHz) δ (ppm): 13.7-13.6 (m, 1H), 8.62-8.51 (m, 1H), 8.03-7.86(m, 1H),7.47-7.25 (m, 4H), 7.15-7.10 (m, 1H), 7.01-6.95 (m, 4H), 4.30-4.15 (m,3H), 2.22-2.10 (m, 1H), 1.88-1.62 (m, 4H). 8-a

N- ((1R,4R,5S)- 2-cyano-2- azabicyclo[2.1.1] hexan-5- yl)-5-(2-phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 386 ¹HNMR (DMSO-d₆, 400MHz) δ (ppm): 13.7 (br s, 1H), 7.94-7.88 (m, 2H), 7.41-7.28 (m, 4H),7.16-7.12 (m, 1H), 7.03-6.92 (m, 4H), 4.20-4.19 (m, 1H), 3.83-3.82 (m,1H), 3.45-3.43 (m, 1H), 2.94-2.92 (m, 1H), 1.78-1.76 (m, 1H), 1.32-1.29(m, 1H). 8-b

N- ((1S,4S,5R)- 2-cyano-2- azabicyclo[2.1.1] hexan-5- yl)-5-(2-phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 386 ¹HNMR (DMSO-d₆, 400MHz) δ (ppm): 13.6 (br s, 1H), 7.94-7.88 (m, 2H), 7.41-7.29 (m, 4H),7.16-7.12 (m, 1H), 7.03-6.98 (m, 4H), 4.20-4.19 (m, 1H), 3.83-3.82 (m,1H), 3.45-3.43 (m, 1H), 2.94-2.92 (m, 1H), 1.78-1.76 (m, 1H), 1.32-1.29(m, 1H). 9-a

N-[(7S)-5- cyano-2-oxa- 5- azaspiro[3.4] octan-7-yl]-5- (2- phenoxyphe-nyl)-1H- pyrazole-3- carboxamide 416 ¹H-NMR (CD₃OD, 400 MHz) δ (ppm):7.80-7.77 (m, 1H), 7.39-7.35 (m, 3H), 7.28-7.25 (m, 1H), 7.16-7.13 (m,2H), 7.03-6.97 (m, 3H), 4.97-4.93 (m, 2H), 4.74-4.70 (m, 2H), 4.55-4.50(m, 1H), 3.86-3.81 (m, 1H), 3.54-3.50 (m, 1H), 2.68-2.63 (m, 1H),2.53-2.48 (m, 1H). 9-b

N-[(7R)-5- cyano-2-oxa- 5- azaspiro[3.4] octan-7-yl]-5- (2- phenoxyphe-nyl)-1H- pyrazole-3- carboxamide 416 ¹H-NMR (CD30D, 400 MHz) δ (ppm):7.80-7.77 (m, 1H), 7.39-7.35 (m, 3H), 7.28-7.25 (m, 1H), 7.16-7.13 (m,2H), 7.03-6.97 (m, 3H), 4.97-4.90 (m, 2H), 4.74-4.70 (m, 2H), 4.55-4.51(m, 1H), 3.86-3.82 (m, 1H), 3.54-3.50 (m, 1H), 2.68-2.63 (m, 1H),2.53-2.48 (m, 1H). 13-a

N- ((1S,4R,5S)- 2-cyano-2- azabicyclo[3.1.0] hexan-4- yl)-3-(2-phenoxyphe- nyl)-1H- pyrazole-5- carboxamide 386 ¹H-NMR (DMSO-d_(6,) 400MHz) δ (ppm): ¹H-NMR (DMSO-d_(6,) 400 MHz) δ (ppm): 13.75-13.61 (m, 1H),8.55-8.20 (m, 1H), 8.05-7.87 (m, 1H), 7.45-7.30 (m, 4H), 7.16-7.14 (m,1H), 7.03-6.97 (m, 3H), 6.95-6.85 (m, 1H), 4.80-4.77 (m, 1H), 3.72-3.67(m, 1H), 3.51-3.49 (m, 1H), 3.12-3.08 (m, 1H), 1.90-1.80 (m, 1H),1.40-1.20 (m, 1H), 0.75-0.60 (m, 1H). 13-b

N- ((1R,4S,5R)- 2-cyano-2- azabicyclo[3.1.0] hexan-4- yl)-3-(2-phenoxyphe- nyl)-1H- pyrazole-5- carboxamide 20-a

N-((3aR,6aS)- 2- cyanohexahy- drocyclopenta [c]pyrrol- 3a(1H)-yl)-5- (2-phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 414 ¹H-NMR (DMSO-d_(6,) 400MHz) δ (ppm): 13.70-13.58 (m, 1H), 8.55-8.21 (m, 1H), 8.03-7.86 (m, 1H),7.45-7.13 (m, 5H), 7.04-6.92 (m, 3H), 3.70-3.66 (m, 2H), 3.54- 3.49 (m,1H), 3.16-3.14 (m, 1H), 1.78-1.74 (m, 1H), 2.93-2.81 (m, 1H), 2.09- 1.90(m, 3H), 1.71-1.63 (m, 2H), 1.41-1.37 (m, 1H). 20-b

N-((3aS,6aR)- 2- cyanohexahy- drocyclopenta [c]pyrrol- 3a(1H)-yl)-5- (2-phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 414 ¹H-NMR (DMSO-d_(6,) 400MHz) δ (ppm): 13.62 (br s, 1H), 8.33 (br s, 1H), 7.94- 7.93 (m, 1H),7.42-7.30 (m, 3H), 7.28-7.26 (m, 1H), 7.16-7.14 (m, 1H), 7.12 (br s,1H), 7.08-6.98 (m, 3H), 3.70-3.64 (m, 2H), 3.52-3.50 (m, 1H), 3.16-3.13(m, 1H), 2.91-2.89 (m, 1H), 2.05- 1.89 (m, 3H), 1.73-1.63 (m, 2H),1.41-1.37 (m, 1H).

Example 3 Preparation ofN-((1R,5S)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-earboxamide(6-a) andN-((1S,5R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide(6-b)

Compounds 6-a and 6-b were prepared by the following route:

Step 1. Methyl5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate

2-(Trimethylsilyl)ethoxymethyl chloride (12.2 mL, 68.8 mmol) was addeddropwise to a 0° C. solution of methyl 5-bromo-1H-pyrazole-3-carboxylate(5.00 g, 24.5 mmol) and potassium carbonate (18.0 g, 130 mmol) in DMF(10 mL). The resulting mixture was stirred for 14 h at 25° C. Thereaction was quenched with water (20 mL) at 0° C. The resulting mixturewas extracted with ethyl acetate (3×30 mL). The combined organic layerswere washed with brine (2×100 mL), dried over anhydrous sodium sulfate,and filtered. The filtrate was concentrated under vacuum. The residuewas purified by silica gel chromatography (eluting with 15:1 petroleumether/ethyl acetate) to afford methyl5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate(6.20 g, 76%) as a yellow oil. LCMS (ES, m/z): 335, 337 [M+H]⁺.

Step 2. Methyl5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate

A solution of methyl5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate(6.20 g, 18.5 mmol), (2-phenoxyphenyl)boronic acid (4.96 g, 23.2 mmol),XPhos-Pd-G3 (3.12 g, 36.9 mmol) and potassium phosphate tribasic (25.4mg, 37.1 mmol) in dioxane (120 mL) and water (24 mL) was stirred for 15h at 100° C. in an oil bath. The mixture was cooled to 25° C. Theresulting mixture was concentrated under vacuum. The residue was dilutedwith water (30 mL). The resulting mixture was extracted with ethylacetate (3×30 mL). The combined organic layers were dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purified byreverse phase chromatography (Column:)(Bridge Shield RP18 OBD Column, 5μm, 30×150 mm; Mobile phase, A: water (containing 0.05% ammoniumhydrogen) and B: acetonitrile (5% B to 72% over 20 min); Detector: UV220 and 254 nm) to afford methyl5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylateas a yellow solid (3.20 g, 41%). LCMS (ES, m/z): 425 [M+H]⁺.

Step 3.5-(2-Phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylicacid

A solution of methyl5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate(1.40 g, 3.30 mmol) and lithium hydroxide (810 mg, 34.0 mmol) in THF(60.0 mL), water (15.0 mL), and methanol (30.0 mL) was stirred for 4 hat 50° C. The mixture was cooled to 25° C. and concentrated undervacuum. The pH value of the residue was adjusted to 3-4 with 3 N aqueoushydrochloric acid solution. The resulting mixture was extracted withethyl acetate (3×30 mL). The combined organic layers were washed withbrine (2×100 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated. The residue was purified by silica gel chromatography(eluting with 2:1 petroleum ether/ethyl acetate) to afford5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylicacid as an off-white solid (1.00 g, 74%). LCMS (ES, m/z): 411 [M+H]⁺.

Step 4. tert-Butyl1-(5-(2-phenoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamido)-3-azabicyclo[3.2.0]heptane-3-carboxylate

A solution of5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylicacid (300 mg, 0.723 mmol), tert-butyl1-amino-3-azabicyclo[3.2.0]heptane-3-carboxylate (154 mg, 0.723 mmol),HATU (275 mg, 0.723 mmol) and N,N-diisopropylethylamine (0.239 mL, 1.45mmol) in DMF (2 mL) was stirred for 40 min at 25° C. The reaction wasquenched with water (5 mL). The resulting mixture was extracted withethyl acetate (3×15 mL). The combined organic layers were washed withbrine (2×30 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated. The residue was purified by silica gel chromatography(eluting with 4:1 petroleum ether/ethyl acetate) to afford tert-butyl1-(5-(2-phenoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamido)-3-azabicyclo[3.2.0]heptane-3-carboxylateas an off-white solid (350 mg, 80%). LCMS (ES, m/z): 605 [M+H]⁺.

Step 5.N-(3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide2,2,2-trifluoroacetate

A solution of tert-butyl1-(5-(2-phenoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamido)-3-azabicyclo[3.2.0]heptane-3-carboxylate(350 mg, 0.579 mmol) in trifluoroacetic acid (1 mL) and dichloromethane(3 mL) was stirred for 30 min at 25° C. The resulting mixture wasconcentrated under vacuum to affordN-(3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide2,2,2-trifluoroacetate as a brown oil (360 mg, crude). LCMS (ES, m/z):375 [M+H]t

Step 6. N-((1R, 5 S)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide(6-a) andN-((1S,5R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide(6-b)

Cyanogen bromide (72.8 mg, 0.687 mmol) was added dropwise to a 0° C.solution ofN-(3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide2,2,2-trifluoroacetate (350 mg, 0.763 mmol) and sodium bicarbonate (785mg, 9.25 mmol) in DMF (2 mL). The mixture was stirred for 1 h at 25° C.The solids were filtered out. The filtrate was directly purified byPrep-HPLC (Column:)(Bridge Shield RP18 OBD Column, 5 μm, 30×150 mm;Mobile phase, A: water (containing 0.05% ammonium hydrogen) and B:acetonitrile (35% B to 65% over 7 min); Detector: UV 220 and 254 nm) toaffordN-(3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamideas a white solid (70.0 mg). This material was separated by chiral-HPLC(Column: Chiralpak IG, 2*25 cm, 5 μm; Mobile Phase, A: MTBE and B: EtOH(hold 15% in 24 min); Flow rate: 20 mL/min; Detector: 220/254 nm). Thefirst elutinig isomer was collected, and the absolute stereochemistrywas arbitrarily assigned as (1R,5S):N-((1R,5S)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide(RT₁=10.9 min) as a white solid (6-a, 28.5 mg, 10%). LCMS (ES, m/z): 400[M+H]⁺. ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 13.68-13.62 (m, 1H),8.92-8.61 (m, 1H), 8.03-7.86 (m, 1H), 7.42-7.23 (m, 4H), 7.21-7.12 (m,1H), 7.03-6.89 (m, 4H) , 3.73-3.70 (m, 1H), 3.68-3.56 (m, 1H), 3.39-3.31(m, 2H), 3.08-3.05 (m, 1H), 2.34-2.31 (m, 1H), 2.20-2.08 (m, 2H),1.61-1.58 (m, 1H). The second eluting isomer was collected, and theabsolute stereochemistry was arbitrarily assigned as (1S,5R):N-((1S,5R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide(RT₂=12.7 min) as a white solid (6-b, 20.6 mg, 8%). LCMS (ES, m/z): 400[M+H]⁺. ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 13.68-13.62 (m, 1H),8.92-8.61 (m, 1H), 8.03-7.86 (m, 1H), 7.42-7.29 (m, 4H), 7.21-7.12 (m,1H), 7.04-6.89 (m, 4H) , 3.73-3.70 (m, 1H), 3.68-3.54 (m, 1H), 3.39-3.31(m, 2H), 3.08-3.05 (m, 1H), 2.34-2.31 (m, 1H), 2.20-2.08 (m, 2H),1.61-1.58 (m, 1H). Alternatively, the absolute stereochemistry of thefirst and second eluting isomers could have been arbitrarily assigned as(1S,5R) and (1R,5S), respectively.

Example 4 Preparation ofN-((1S,5R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide(3-a) andN-((1R,5S)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide(3-b)

Compounds 3-a and 3-b were prepared by the following route:

Step 1. Methyl5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate

2-(Trimethylsilyl)ethoxymethyl chloride (12.2 mL, 68.8 mmol) was addeddropwise to a 0° C. solution of methyl 5-bromo-1H-pyrazole-3-carboxylate(5.00 g, 24.5 mmol) and potassium carbonate (18.0 g, 130 mmol) in DMF(10 mL). The resulting mixture stirred for 14 h at 25° C. The reactionwas quenched with water (20 mL) at 0° C. The resulting mixture wasextracted with ethyl acetate (3×30 mL). The combined organic layers werewashed with brine (2×100 mL), dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under vacuum. The residue waspurified by silica gel chromatography (eluting with 15:1 petroleumether/ethyl acetate) to afford methyl5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate(6.20 g, 76%) as a yellow oil. LCMS (ES, m/z): 335, 337 [M+H]⁺.

Step 2. Methyl5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate

A solution of methyl5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate(6.20 g, 18.5 mmol), (2-phenoxyphenyl)boronic acid (4.96 g, 23.2 mmol),XPhos-Pd-G3 (3.12 g, 36.9 mmol) and potassium phosphate tribasic (25.4mg, 37.1 mmol) in dioxane (120 mL) and water (24 mL) was stirred for 15h at 100° C. in an oil bath. The mixture was cooled to 25° C. Theresulting mixture was concentrated under vacuum. The residue was dilutedwith water (30 mL). The resulting mixture was extracted with ethylacetate (3×30 mL). The combined organic layers were dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purified byreverse phase chromatography (Column:)(Bridge Shield RP18 OBD Column, 5μm, 30×150 mm; Mobile phase, A: water (containing 0.05% ammoniumhydrogen) and B: acetonitrile (5% B to 72% over 20 min); Detector: UV220 and 254 nm) to afford methyl5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylateas a yellow solid (3.20 g, 41%). LCMS (ES, m/z): 425 [M+H]⁺.

Step 3.5-(2-Phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylicacid

A solution of methyl5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate(1.40 g, 3.30 mmol) and lithium hydroxide (810 mg, 34.0 mmol) in THF(60.0 mL), water (15.0 mL), and methanol (30.0 mL) was stirred for 4 hat 50° C. The mixture was cooled to 25° C. and concentrated undervacuum. The pH value of the residue was adjusted to 3-4 with 3 N aqueoushydrochloric acid solution. The resulting mixture was extracted withethyl acetate (3×30 mL). The combined organic layers were washed withbrine (2×100 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated. The residue was purified by silica gel chromatography(eluting with 2:1 petroleum ether/ethyl acetate) to afford5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylicacid as an off-white solid (1.00 g, 74%). LCMS (ES, m/z): 411 [M+H]⁺.

Step 4.tert-butyl-(5-(2-phenoxyphenyl)-14(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamido)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A solution of5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylicacid (300 mg, 0.723 mmol), tert-butyl1-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (145 mg, 0.723 mmol),HATU (278 mg, 0.723 mmol) and N,N-diisopropylethylamine (0.242 mL, 1.47mmol) in DMF (3 mL) was stirred for 30 min at 25° C. The reaction wasquenched with water (10 mL) at 25° C. The resulting mixture wasextracted with ethyl acetate (3×10 mL). The combined organic layers werewashed with brine (2×30 mL), dried over anhydrous sodium sulfate,filtered, and concentrated. The residue was purified by silica gelchromatography (eluting with 4:1 petroleum ether/ethyl acetate) toafford tert-butyl1-(5-(2-phenoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamido)-3-azabicyclo[3.1.0]hexane-3-carboxylateas an off-white solid (280 mg, 67%). LCMS (ES, m/z): 591 [M+H]⁺.

Step 5.N-(3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide2,2,2-trifluoroacetate

A solution of tert-butyl1-(5-(2-phenoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamido)-3-azabicyclo[3.1.0]hexane-3-carboxylate(280 mg, 0.475 mmol) in trifluoroacetic acid (1 mL) and dichloromethane(3 mL) was stirred for 2 h at 25° C. The resulting mixture wasconcentrated under vacuum to affordN-(3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide2,2,2-trifluoroacetate as a yellow oil (285 mg, crude). LCMS (ES, m/z):361 [M+H]⁺.

Step 6.N-((1S,5R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide(3-a) andN-((1R,5S)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide(3-b)

Cyanogen bromide (58.5 mg, 0.552 mmol) was added dropwise to a 0° C.solution ofN-(3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide2,2,2-trifluoroacetate (280 mg, 0.613mmo1) and sodium bicarbonate (653mg, 7.69 mmol) in DMF (2 mL). The mixture was stirred for 1 h at 25° C.The reaction was cooled to 0° C. and quenched with water (10 mL). Theresulting mixture was extracted with ethyl acetate (3×10 mL). Thecombined organic layers were washed with brine (20 mL), dried overanhydrous sodium sulfate, filtered, and concentrated. The residue waspurified by Prep-HPLC (Column:)(Bridge Shield RP18 OBD Column, 5 μm,30×150 mm; Mobile phase, A: water (containing 0.05% ammonium hydrogen)and B: acetonitrile (28% B to 48% over 7 min); Detector: UV 220 and 254nm) to affordN-(3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamideas a white solid (60.0 mg). This material was separated by chiral-HPLC(Column: Chiralpak IG, 2*25 cm, 5 μm; Mobile Phase, A: MTBE and B: EtOH(hold 30% in 10.5 min); Flow rate: 13 mL/min; Detector: 220/254 nm). Thefirst eluting isomer was collected, and the absolute stereochemistry wasarbitrarily assigned as (1S,5R):N-((1S,5R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide(RT₁=6.45 min) as a pink solid (3-a, 30.3 mg, 14%). LCMS (ES, m/z): 386[M+H]⁺. ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 13.72-13.64 (m, 1H),9.08-8.70 (m, 1H), 8.05-7.85 (m, 1H), 7.44-7.29 (m, 4H), 7.20-7.12 (m,1H), 7.04-6.87 (m, 4H), 3.69-3.66 (m, 1H), 3.57-3.48 (m, 3H), 1.78-1.74(m, 1H), 1.17-1.14 (m, 1H), 0.87-0.82 (m, 1H). The second eluting isomerwas collected, and the absolute stereochemistry was arbitrarily assignedas (1R,5S);N-((1R,5S)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide(RT₂=8.97 min) (3-b, 29.9 mg, 14%) as a white solid. LCMS (ES, m/z): 386[M+H]⁺. ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 13.72-13.64 (m, 1H),9.08-8.70 (m, 1H), 8.05-7.85 (m, 1H), 7.44-7.29 (m, 4H), 7.22-7.12 (m,1H), 7.04-6.87 (m, 4H), 3.69-3.66 (m, 1H), 3.57-3.51 (m, 3H), 1.78-1.74(m, 1H), 1.17-1.14 (m, 1H), 0.87-0.82 (m, 1H). Alternatively, theabsolute stereochemistry of the first and second eluting isomers couldhave been arbitrarily assigned as (1R,5S) and (1S,5R), respectively.

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only.

What is claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein R^(a), R^(b),R^(c), R^(d), R^(e), R^(f), R_(g) and R^(h) are defined as follows: (i)R^(a) and R^(b) form a C₁-C₄ alkylene group between the atoms to whichthey are attached, wherein said C₁-C₄ alkylene group is substituted with0-4 substituents selected from the group consisting of halogen, C₁-C₃alkyl, and C₁-C₃ haloalkyl; and R^(c), R^(d), R^(e), R^(f), R^(g), andR^(h) are each independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃haloalkyl; or (ii) R^(a) and R^(c) form a C₁-C₂ alkylene group betweenthe atoms to which they are attached, wherein said C₁-C₂ alkylene groupis substituted with 0-4 substituents selected from the group consistingof halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and R^(b), R^(c), R^(d),R^(f), R^(g), and R^(h) are each independently hydrogen, halogen, C₁-C₃alkyl, or C₁-C₃ haloalkyl; or (iii) R^(a) and R^(g) form a C₁-C₃alkylene group between the atoms to which they are attached, whereinsaid C₁-C₃ alkylene group is substituted with 0-4 substituents selectedfrom the group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl;and R^(b), R^(c), R^(d), R^(e), R^(f), and R^(h) are each independentlyhydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl; or (iv) R^(b) andR^(c) form a C₁-C₄ alkylene group between the atoms to which they areattached, wherein said C₁-C₄ alkylene group is substituted with 0-4substituents selected from the group consisting of halogen, C₁-C₃ alkyl,and C₁-C₃ haloalkyl; and R^(a), R^(d), R^(e), R^(f), R^(g), and R^(h)are each independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃haloalkyl; or (v) R^(b) and Re form a C₁-C₃ alkylene group between theatoms to which they are attached, wherein said C₁-C₃ alkylene group issubstituted with 0-4 substituents selected from the group consisting ofhalogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and R^(a), R^(c), R^(d),R^(f), R^(g), and R^(h) are each independently hydrogen, halogen, C₁-C₃alkyl, or C₁-C₃ haloalkyl; or (vi) R^(b) and R^(g) form a C₁-C₄ alkylenegroup between the atoms to which they are attached, wherein said C₁-C₄alkylene group is substituted with 0-4 substituents selected from thegroup consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; andR^(a), R^(c), R^(d), R^(e), R^(f), and R^(h) are each independentlyhydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl; or (vii) R^(c) andR^(d) together with the atom to which they are attached, form a 3-6membered cycloalkyl or heterocycloalkyl, wherein said 3-6 memberedcycloalkyl or heterocycloalkyl is substituted with 0-4 substituentsselected from the group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃haloalkyl; and R^(a), R^(b), R^(e), R^(f), R^(g), and R^(h) are eachindependently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl; or(viii) R^(c) and R^(d) together form ═O; and R^(a), R^(b), R^(e), R^(f),R^(g), and R^(h) are each independently hydrogen, halogen, C₁-C₃ alkyl,or C₁-C₃ haloalkyl; or (ix) R^(c) and R^(c) form a C₁-C₄ alkylene groupbetween the atoms to which they are attached, wherein said C₁-C₄alkylene group is substituted with 0-4 substituents selected from thegroup consisting of halogen, C₁-C₃ alkyl, and C₁-C₃ haloalkyl; andR^(a), R^(b), R^(d), R^(f), R^(g), and R^(h) are each independentlyhydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl; or (x) R^(c) andR^(g) form a C₁-C₃ alkylene group between the atoms to which they areattached, wherein said C₁-C₃ alkylene group is substituted with 0-4substituents selected from the group consisting of halogen, C₁-C₃ alkyl,and C₁-C₃ haloalkyl; and R^(a), R^(b), R^(d), R^(e), R^(f), and R^(h)are each independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃haloalkyl; or (xi) R^(c) and R^(f) together with the atom to which theyare attached, form a 3-6 membered cycloalkyl or heterocycloalkyl,wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substitutedwith 0-4 substituents selected from the group consisting of halogen,C₁-C₃ alkyl, and C₁-C₃ haloalkyl; and R^(a), R^(b), R^(c), R^(d), R^(g),and R^(h) are each independently hydrogen, halogen, C₁-C₃ alkyl, orC₁-C₃ haloalkyl; or (xii) R^(c) and R^(f) together form ═O; and R^(a),R^(b), R^(e), R^(d), R^(g), and R^(h) are each independently hydrogen,halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl; or (xiii) R^(c) and R^(g) forma C₁-C₃ alkylene group between the atoms to which they are attached,wherein said C₁-C₃ alkylene group is substituted with 0-4 substituentsselected from the group consisting of halogen, C₁-C₃ alkyl, and C₁-C₃haloalkyl; and R^(a), R^(b), R^(c), R^(d), R^(f), and R^(h) are eachindependently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ haloalkyl; or(xiv) R^(g) and R^(h) together with the atom to which they are attached,form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6membered cycloalkyl or heterocycloalkyl is substituted with 0-4substituents selected from the group consisting of halogen, C₁-C₃ alkyl,and C₁-C₃ haloalkyl; and R^(a), R^(b), R^(c), R^(d), R^(e), and R^(f)are each independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃haloalkyl; or (xv) R^(g) and R^(h) together form ═O; and R^(a), R^(b),R^(c), R^(d), R^(e), and R^(f) are each independently hydrogen, halogen,C₁-C₃ alkyl, or C₁-C₃ haloalkyl; and Ar¹ is phenylene or 5-6 memberedheteroarylene, wherein said phenylene or heteroarylene is substitutedwith m IV groups; and Ar² is phenylene or 5-10 membered heteroarylene,wherein said phenylene or heteroarylene is substituted with n R² groups;L is —O—, —S—, —NR³—, —C(R⁴)₂—, —S(O)₂—, or —S(O)—; M is C₁-C₆ alkyl,C₁-C₆ haloalkyl, 3-6 membered cycloalkyl, phenyl, or 5-6 memberedheteroaryl, wherein said cycloalkyl, phenyl, or heteroaryl issubstituted with p R⁵ groups; each occurrence of R¹, R², and R⁵ isindependently halo, cyano, NO₂, oxo, hydroxyl, —R⁶, —OR⁶, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, —C₁-C₆ alkylene-R⁶, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, —C₀-C₃ alkylene-NR⁶R⁷, —C₀-C₃ alkylene-NR⁷R⁸, —C₀-C₃alkylene-C(O)NR⁶R⁷, —C₀-C₃ alkylene-C(O)NR⁷R⁸, —C₀-C₃alkylene-NR⁷C(O)R⁶, —C₀-C₃ alkylene-NICC(O)R⁸, —C₀-C₃alkylene-NR⁷S(O)₂R⁶, —C₀-C₃ alkylene-C(O)R⁶, —C₀-C₃ alkylene-C(O)R⁷,—C₀-C₃ alkylene-SR⁶, —C₀-C₃ alkylene-S(O)R⁶, —C₀-C₃ alkylene-S(O)₂R⁶,—C₀-C₃ alkylene-S(O)₂R⁷, —C₀-C₃ alkylene-S(O)₂NR⁶R⁷, —C₀-C₃alkylene-S(O)₂NR⁷R⁸, —C₀-C₃ alkylene-NR⁷C(O)NR⁸R⁹, —C₀-C₃alkylene-NR⁷S(O)₂NR⁸R⁹, —C₀-C₃ alkylene-C(O)OR⁷, —C₀-C₃alkylene-C(O)OR⁶, —C₀-C₃ alkylene-OC(O)R⁷, —C₀-C₃ alkylene-OC(O)R⁶,—C₀-C₃ alkylene-NR⁷C(O)OR⁸, or —C₀-C₃ alkylene-NR⁷S(O)₂R⁸; R³ is H,C₁-C₆ alkyl, or C₁-C₆ haloalkyl; each R⁴ is independently H, C₁-C₆alkyl, or C₁-C₆ haloalkyl, or two R⁴ groups together with the carbonatom to which they are attached form a 3-6 membered cycloalkyl orheterocycloalkyl; each R⁶ is 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, 6-10 membered aryl, or 3-8 membered cycloalkyl,wherein said heteroaryl, heterocycloalkyl, aryl, or cycloalkyl isoptionally substituted with 1-5 substituents independently selected fromthe group consisting of halo, oxo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10membered aryl, 3-8 membered cycloalkyl, —NR¹⁰C(O)NR¹¹R¹², —NR¹⁰R¹¹,—C(O)R¹⁰, —NR¹⁰C(O)R¹¹, —NR¹⁰C(O)OR¹¹, —S(O)₂R¹⁰, —C(O)NR¹⁰R¹¹,—C(O)OR¹⁰, —S(O)₂NR¹⁰R¹¹, —NR¹⁰S(O)₂R¹¹, —OR¹⁰, —OC(O)R¹⁰, —OS(O)₂R¹⁰,—OC(O)NR^(M)R¹¹, —OC(O)OR¹⁰, —OS(O)₂NR¹⁰R¹¹, —C(O)NR¹⁰C(O)NR¹¹R¹²,—C(O)C(O)R¹⁰, —C(O)NR¹⁰C(O)R¹¹, —C(O)NR¹⁰C(O)OR¹¹, —C(O)S(O)₂R¹⁰,—C(O)C(O)NR¹⁰R¹¹, —C(O)C(O)OR¹⁰, —C(O)S(O)₂NR¹⁰R¹¹, —C(O)NR¹⁰S(O)₂R¹¹,—C₁-C₆ alkylene-R¹⁰, —C₁-C₆ alkylene-NR¹⁰C(O)NR¹¹R¹², —C₁-C₆alkylene-NR¹⁰R¹¹, —C₁-C₆ alkylene-C(O)R¹⁰, —C₁-C₆ alkylene-NR¹⁰C(O)R¹¹,—C₁-C₆ alkylene-NR¹⁰C(O)OR¹¹, —C₁-C₆ alkylene-S(O)₂R¹⁰, —C₁-C₆alkylene-C(O)NR¹⁰R¹¹, —C₁-C₆ alkylene-C(O)OR¹⁰, —C₁-C₆alkylene-S(O)₂NR¹⁰R¹¹, —C₁-C₆ alkylene-NR¹⁰S(O)₂R¹¹, —C₁-C₆alkenylene-R¹⁰, —C₁-C₆ alkenylene-NR¹⁰C(O)NR¹¹R¹², —C₁-C₆alkenylene-NR¹⁰R¹¹, —C₁-C₆ alkenylene-C(O)R¹⁰, —C₁-C₆alkenylene-NR¹⁰C(O)R¹¹, —C₁-C₆ alkenylene-NR¹⁰C(O)OR¹¹, —C₁-C₆alkenylene-S(O)₂R¹⁰, —C₁-C₆ alkenylene-C(O)NR¹⁰R¹¹, —C₁-C₆alkenylene-C(O)OR¹⁰, —C₁-C₆ alkenylene-S(O)₂NR¹⁰R¹¹, and —C₁-C₆alkenylene-NR¹⁰S(O)₂R¹¹; each R⁷, R⁸, and R⁹ is independently hydrogenor C₁-C₆ alkyl; each R¹⁰, R¹¹, and R¹² is independently hydrogen, C₁-C₆alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10membered aryl, or 3-8 membered cycloalkyl; m is 0-4; n is 0-4; and p is0-4.
 2. The compound of claim 1, wherein the compound is of formula(I-B):

or a pharmaceutically acceptable salt thereof, wherein: X¹ is C or N; X²is CH, CR¹, O, S, N, NH, or NR¹, as valency permits; X³ is CH, CR¹, O,S, N, NH, or NR¹, as valency permits; X⁴ is C or N; X⁶ is CH, CR¹, O, S,N, NH, or NR¹, as valency permits; Y³ is CH, CR², or N; Y⁴ is CH, CR²,or N; Y⁵ is CH, CR², or N; Y⁶ is CH, CR², or N.
 3. The compound of claim1 or 2, wherein the compound is of formula (I-C):

or a pharmaceutically acceptable salt thereof.
 4. The compound of anyone of claims 1-3, wherein the compound is of formula (I-E):

or a pharmaceutically acceptable salt thereof.
 5. The compound of anyone of claims 1-4, wherein R^(b) and R^(c) form a C₁-C₄ alkylene groupbetween the atoms to which they are attached, and R^(a), R^(d), R^(e),R^(f), R^(g), and R^(h) are each hydrogen.
 6. The compound of any one ofclaims 1-5, wherein the compound is of formula (I-1):

or a pharmaceutically acceptable salt thereof, wherein R^(j), R^(k),R^(m), and R^(n) are each independently hydrogen, halogen, C₁-C₃ alkyl,or C₁-C₃ haloalkyl.
 7. The compound of claim 6, wherein the compound isof formula (I-B-1):

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim7, wherein the compound is of formula (I-C-1):

or a pharmaceutically acceptable salt thereof.
 9. The compound of anyone of claims 6-8, wherein R^(a), R^(d), R^(e), R^(f), R^(g), R^(h),R^(j), R^(k), R^(m), and R^(n) are each hydrogen.
 10. The compound ofany one of claims 1-5, wherein the compound is of formula (I-2):

or a pharmaceutically acceptable salt thereof, wherein R^(j) and R^(k)are each independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃haloalkyl.
 11. The compound of claim 10, wherein the compound is offormula (I-B-2):

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim11, wherein the compound is of formula (I-C-2):

or a pharmaceutically acceptable salt thereof.
 13. The compound of anyone of claims 10-12, wherein R^(a), R^(d), R^(e), R^(f), R^(g), R^(h),R^(j) and R^(k) are each hydrogen.
 14. The compound of any one of claims1-5, wherein the compound is of formula (I-3):

or a pharmaceutically acceptable salt thereof, wherein R^(j) R^(k),R^(m), R^(n), R^(o), and R^(p) are each independently hydrogen, halogen,C₁-C₃ alkyl, or C₁-C₃ haloalkyl.
 15. The compound of claim 14, whereinthe compound is of formula (I-B-3):

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim15, wherein the compound is of formula (I-C-3):

or a pharmaceutically acceptable salt thereof.
 17. The compound of anyone of claims 14-16, wherein R^(a), R^(d), R^(e), R^(f), R^(g), R^(h),R^(j), R^(k), R^(m), R^(n), R^(o), and R^(p) are each hydrogen.
 18. Thecompound of any one of claims 1-4, wherein R^(c) and R^(e) form a C₁-C₄alkylene group between the atoms to which they are attached; and R^(a),R^(b), R^(d), R^(f), R^(g), R^(g) and R^(h) are each hydrogen.
 19. Thecompound of any one of claims 1-4 and 18, wherein the compound is offormula (I-4):

or a pharmaceutically acceptable salt thereof, wherein R^(q) and R^(r)are each independently hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃haloalkyl.
 20. The compound of claim 19, wherein the compound is offormula (I-B-4):

or a pharmaceutically acceptable salt thereof.
 21. The compound of claim20, wherein the compound is of formula (I-C-4):

or a pharmaceutically acceptable salt thereof.
 22. The compound of anyone of claims 19-21, wherein R^(a), R^(b), R^(d), R^(f), R^(g), R^(h),R^(q), and R^(r) are each hydrogen.
 23. The compound of any one ofclaims 1-4, wherein R^(a) and R^(e) form a C₁-C₂ alkylene group betweenthe atoms to which they are attached; and R^(b), R^(c), R^(d), R^(f),R^(g), and R^(h) are each hydrogen.
 24. The compound of any one ofclaims 1-4, wherein R^(c) and R^(d) together with the atom to which theyare attached, form a 3-6 membered cycloalkyl or heterocycloalkyl; andR^(a), R^(b), R^(e), R^(f), R^(g), and R^(h) are each hydrogen.
 25. Thecompound of any one of claims 1-4, wherein R^(c) and R^(g) form a C₁-C₃alkylene group between the atoms to which they are attached; and R^(a),R^(b), R^(d), R^(e), R^(f), and R^(h) are each hydrogen.
 26. Thecompound of any one of claims 1-4, wherein R^(e) and R^(f) together withthe atom to which they are attached, form a 3-6 membered cycloalkyl orheterocycloalkyl; and R^(a), R^(b), R^(e), R^(d), R^(g), and R^(h) areeach hydrogen.
 27. The compound of any one of claims 1-4, wherein R^(e)and R^(g) form a C₁-C₃ alkylene group between the atoms to which theyare attached; and R^(a), R^(b), R^(c), R^(d), R^(f), and R^(h) are eachhydrogen.
 28. The compound of any one of the preceding claims, whereinAr¹ is 5-6 membered heteroarylene.
 29. The compound of claim 28, whereinAr¹ is 5-membered heteroarylene.
 30. The compound of any one of claims1-27, wherein Ar¹ is phenylene.
 31. The compound of any one of thepreceding claims, wherein Ar² is 5-10 membered heteroarylene.
 32. Thecompound of any one of claims 1-30, wherein Ar² is phenylene.
 33. Thecompound of any one of the preceding claims, wherein L is —O—, —S—, or—NH—.
 34. The compound of claim 33, wherein L is —O—.
 35. The compoundof any one of the preceding claims, wherein M is 3-6 memberedcycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said cycloalkyl,phenyl, or heteroaryl is substituted with p R⁵ groups.
 36. The compoundof claim 35, wherein M is phenyl substituted with p R⁵ groups.
 37. Thecompound of claim 36, wherein M is phenyl.
 38. The compound of any oneof the preceding claims, wherein each occurrence of R¹, R², and R⁵ isindependently selected from halo, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ hydroxyalkyl.
 39. The compound of anyone of the preceding claims, wherein m is
 0. 40. The compound of any oneof the preceding claims, wherein n is
 0. 41. The compound of any one ofthe preceding claims, whereinp is 0 or
 1. 42. The compound of claim 41,whereinp is
 0. 43. The compound of any one of the preceding claims,wherein

is selected from:


44. A compound, or pharmaceutically acceptable salt thereof, selectedfrom Table
 1. 45. A compound, or pharmaceutically acceptable saltthereof, selected from Table
 2. 46. A pharmaceutical compositioncomprising the compound of any one of claims 1-45, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 47.A method of inhibiting USP30 in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of thecompound of any one of claims 1-45, or a pharmaceutically acceptablesalt thereof, or the pharmaceutical composition of claim
 46. 48. Amethod of treating a neurodegenerative disorder in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of the compound of any one of claims 1-45, or apharmaceutically acceptable salt thereof, or the pharmaceuticalcomposition of claim
 46. 49. The method of claim 48, wherein theneurodegenerative disorder is Parkinson's disease.